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AISC Team B1 5

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SDHD

SDHD Succinate dehydrogenase cytochrome b small subunit, mitochondrial (CybS), also known as succinate dehydrogenase complex subunit D (SDHD), is a protein that in humans is encoded by the SDHD gene. Names previously used for SDHD were PGL and PGL1. Succinate dehydrogenase is an important enzyme in both the citric acid cycle and the electron transport chain. # Structure The SDHD gene is located on chromosome 11 at locus 11q23 and it spans 8,978 base pairs. There are pseudogenes for this gene on chromosomes 1, 2, 3, 7, and 18. The SDHD gene produces a 17 kDa protein composed of 159 amino acids. The SDHD protein is one of the two integral transmembrane subunits anchoring the four-subunit succinate dehydrogenase (Complex II) protein complex to the matrix side of the mitochondrial inner membrane. The other transmembrane subunit is SDHC. The SDHC/SDHD dimer is connected to the SDHB electron transport subunit which, in turn, is connected to the SDHA subunit. # Function SDHD forms part of the transmembrane protein dimer with SDHC that anchors Complex II to the inner mitochondrial membrane. The SDHC/SDHD dimer provides binding sites for ubiquinone and water during electron transport at Complex II. Initially, SDHA oxidizes succinate via deprotonation at the FAD binding site, leaving fumarate, loosely bound to the active site, free to exit the protein. The electrons derived from succinate tunnel along the relay in the SDHB subunit until they reach the iron sulfur cluster. The electrons are then transferred to an awaiting ubiquinone molecule at the active site in the SDHC/SDHD dimer. The O1 carbonyl oxygen of ubiquinone is oriented at the active site (image 4) by hydrogen bond interactions with Tyr83 of SDHD. The presence of electrons in the iron sulphur cluster induces the movement of ubiquinone into a second orientation. This facilitates a second hydrogen bond interaction between the O4 carbonyl group of ubiquinone and Ser27 of subunit C. Following the first single electron reduction step, a semiquinone radical species is formed. The second electron arrives from the cluster to provide full reduction of the ubiquinone to ubiquinol. # Clinical significance Mutations in the SDHD gene can cause familial paraganglioma. Germline mutations in SDHD were first linked to hereditary paraganglioma in 2000. Since then, it has been shown that mutations in SDHB and to a lesser degree SDHC can cause paranglioma as well as familial pheochromocytoma. Notably, the tumor spectrum is different for the different mutations. SDHB mutations often lead to metastatic disease that is extra-adrenal, while SDHD mutation related tumors are more typically benign, originating in the head and neck. The exact mechanism for tumorigenesis is not determined, but it is suspected that malfunction of the SDH complex can cause a hypoxic response in the cell that leads to tumor formation. Mutations in the SDHB, SDHC, SDHD, and SDHAF2 genes lead to the loss or reduction of SDH enzyme activity. Because the mutated SDH enzyme cannot convert succinate to fumarate, succinate accumulates in the cell. As a result, the hypoxia pathways are triggered in normal oxygen conditions, which lead to abnormal cell growth and tumor formation. People living at higher altitudes (for example, the Andes mountains) are known to have an increased rate of benign paraganglioma, with the rate of disease increasing with the altitude of the population. At least five variants in the SDHD gene have been identified in people with Cowden syndrome or a similar disorder called Cowden-like syndrome. These conditions are characterized by multiple tumor-like growths called hamartomas and an increased risk of developing certain cancers. When Cowden syndrome and Cowden-like syndrome are caused by SDHD gene mutations, the conditions are associated with a particularly high risk of developing breast and thyroid cancers. The SDHD gene variants associated with Cowden syndrome and Cowden-like syndrome change single amino acids in the SDHD protein, which likely alters the function of the SDH enzyme. Studies suggest that the defective enzyme could allow cells to grow and divide unchecked, leading to the formation of hamartomas and cancerous tumors. However, researchers are uncertain whether the identified SDHD gene variants are directly associated with Cowden syndrome and Cowden-like syndrome. Some of the variants described above have rarely been found in people without the features of these conditions. Mutations in the SDHD gene have been found in a small number of people with Carney-Stratakis syndrome, a hereditary form of a cancer of the gastrointestinal tract called gastrointestinal stromal tumor (GIST). Those with Carney-Stratakis syndrome present with a noncancerous tumor associated with the nervous system called a paraganglioma or pheochromocytoma (a type of paraganglioma). An inherited SDHD gene mutation predisposes an individual to cancer formation. An additional mutation that deletes the normal copy of the gene is needed to cause Carney-Stratakis syndrome. This second mutation, called a somatic mutation, is acquired during a person's lifetime and is present only in tumor cells. Mitochondrial complex II deficiency (MT-C2D), a disorder of the mitochondrial respiratory chain with heterogeneous clinical manifestations, has also been associated with mutations in the SDHD gene. Clinical features include psychomotor regression in infants, poor growth with lack of speech development, severe spastic quadriplegia, dystonia, progressive leukoencephalopathy, muscle weakness, exercise intolerance, cardiomyopathy. Some patients manifest Leigh syndrome or Kearns-Sayre syndrome. # Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles. - ↑ The interactive pathway map can be edited at WikiPathways: "TCACycle_WP78"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}

SDHD Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial (CybS), also known as succinate dehydrogenase complex subunit D (SDHD), is a protein that in humans is encoded by the SDHD gene. Names previously used for SDHD were PGL and PGL1. Succinate dehydrogenase is an important enzyme in both the citric acid cycle and the electron transport chain.[1][2][3] # Structure The SDHD gene is located on chromosome 11 at locus 11q23 and it spans 8,978 base pairs. There are pseudogenes for this gene on chromosomes 1, 2, 3, 7, and 18.[1] The SDHD gene produces a 17 kDa protein composed of 159 amino acids.[4][5] The SDHD protein is one of the two integral transmembrane subunits anchoring the four-subunit succinate dehydrogenase (Complex II) protein complex to the matrix side of the mitochondrial inner membrane. The other transmembrane subunit is SDHC. The SDHC/SDHD dimer is connected to the SDHB electron transport subunit which, in turn, is connected to the SDHA subunit.[6] # Function SDHD forms part of the transmembrane protein dimer with SDHC that anchors Complex II to the inner mitochondrial membrane. The SDHC/SDHD dimer provides binding sites for ubiquinone and water during electron transport at Complex II. Initially, SDHA oxidizes succinate via deprotonation at the FAD binding site, leaving fumarate, loosely bound to the active site, free to exit the protein. The electrons derived from succinate tunnel along the [Fe-S] relay in the SDHB subunit until they reach the [3Fe-4S] iron sulfur cluster. The electrons are then transferred to an awaiting ubiquinone molecule at the active site in the SDHC/SDHD dimer. The O1 carbonyl oxygen of ubiquinone is oriented at the active site (image 4) by hydrogen bond interactions with Tyr83 of SDHD. The presence of electrons in the [3Fe-4S] iron sulphur cluster induces the movement of ubiquinone into a second orientation. This facilitates a second hydrogen bond interaction between the O4 carbonyl group of ubiquinone and Ser27 of subunit C. Following the first single electron reduction step, a semiquinone radical species is formed. The second electron arrives from the [3Fe-4S] cluster to provide full reduction of the ubiquinone to ubiquinol.[7] # Clinical significance Mutations in the SDHD gene can cause familial paraganglioma.[1] Germline mutations in SDHD were first linked to hereditary paraganglioma in 2000.[8] Since then, it has been shown that mutations in SDHB and to a lesser degree SDHC can cause paranglioma as well as familial pheochromocytoma. Notably, the tumor spectrum is different for the different mutations. SDHB mutations often lead to metastatic disease that is extra-adrenal, while SDHD mutation related tumors are more typically benign, originating in the head and neck.[9] The exact mechanism for tumorigenesis is not determined, but it is suspected that malfunction of the SDH complex can cause a hypoxic response in the cell that leads to tumor formation. Mutations in the SDHB, SDHC, SDHD, and SDHAF2 genes lead to the loss or reduction of SDH enzyme activity. Because the mutated SDH enzyme cannot convert succinate to fumarate, succinate accumulates in the cell. As a result, the hypoxia pathways are triggered in normal oxygen conditions, which lead to abnormal cell growth and tumor formation.[9] People living at higher altitudes (for example, the Andes mountains) are known to have an increased rate of benign paraganglioma, with the rate of disease increasing with the altitude of the population. At least five variants in the SDHD gene have been identified in people with Cowden syndrome or a similar disorder called Cowden-like syndrome. These conditions are characterized by multiple tumor-like growths called hamartomas and an increased risk of developing certain cancers. When Cowden syndrome and Cowden-like syndrome are caused by SDHD gene mutations, the conditions are associated with a particularly high risk of developing breast and thyroid cancers. The SDHD gene variants associated with Cowden syndrome and Cowden-like syndrome change single amino acids in the SDHD protein, which likely alters the function of the SDH enzyme. Studies suggest that the defective enzyme could allow cells to grow and divide unchecked, leading to the formation of hamartomas and cancerous tumors. However, researchers are uncertain whether the identified SDHD gene variants are directly associated with Cowden syndrome and Cowden-like syndrome. Some of the variants described above have rarely been found in people without the features of these conditions.[10] Mutations in the SDHD gene have been found in a small number of people with Carney-Stratakis syndrome, a hereditary form of a cancer of the gastrointestinal tract called gastrointestinal stromal tumor (GIST). Those with Carney-Stratakis syndrome present with a noncancerous tumor associated with the nervous system called a paraganglioma or pheochromocytoma (a type of paraganglioma). An inherited SDHD gene mutation predisposes an individual to cancer formation. An additional mutation that deletes the normal copy of the gene is needed to cause Carney-Stratakis syndrome. This second mutation, called a somatic mutation, is acquired during a person's lifetime and is present only in tumor cells.[10] Mitochondrial complex II deficiency (MT-C2D), a disorder of the mitochondrial respiratory chain with heterogeneous clinical manifestations, has also been associated with mutations in the SDHD gene. Clinical features include psychomotor regression in infants, poor growth with lack of speech development, severe spastic quadriplegia, dystonia, progressive leukoencephalopathy, muscle weakness, exercise intolerance, cardiomyopathy. Some patients manifest Leigh syndrome or Kearns-Sayre syndrome.[11][12][13] # Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles. [§ 1] - ↑ The interactive pathway map can be edited at WikiPathways: "TCACycle_WP78"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}

https://www.wikidoc.org/index.php/SDHD

1c3f72e65af787842e12209eb1ad11c8ac46260c

wikidoc

SDPR

SDPR Cavin-2 or Serum deprivation-response protein (SDPR) is a protein that in humans is encoded by the SDPR gene. Cavin-2 is highly expressed in a variety of human endothelial cells. This gene encodes a calcium-independent phospholipid-binding protein whose expression increases in serum-starved cells. This protein has also been shown to be a substrate for protein kinase C (PKC) phosphorylation. # Function Cavin-2 is required for blood vessel formation (angiogenesis) in humans and zebrafish and required also for the endothelial cell proliferation, migration and invasion in humans. Cavin-2 plays an important role in endothelial cell maintenance by regulating eNOS activity. Cavin-2 controls the generation of nitric oxide (NO) in human endothelial cells by controlling the activity and stability of the protein endothelial nitric-oxide synthase (eNOS). # Secretion Cavin-2 is highly secreted from human endothelial cells (HUVEC), they are secreted through endothelial microparticles (EMPs) but not exosomes and is required for EMP biogenesis. # Clinical significance SDPR is shown to act as a metastasis suppressor by xenograft studies utilizing breast cancer cell lines. SDPR may elicit its metastasis suppressor function by directly interacting with ERK and limiting its pro-survival role. Moreover, it is suggested that SDPR is silenced during breast cancer progression by promoter DNA methylation. Metastasis suppressor role of SDPR may go beyond breast cancer since tumor samples from bladder, colorectal, lung, pancreatic, and ovarian cancers as well as sarcomas also exhibited loss of SDPR expression.

SDPR Cavin-2 or Serum deprivation-response protein (SDPR) is a protein that in humans is encoded by the SDPR gene.[1][2][3] Cavin-2 is highly expressed in a variety of human endothelial cells.[4] This gene encodes a calcium-independent phospholipid-binding protein whose expression increases in serum-starved cells. This protein has also been shown to be a substrate for protein kinase C (PKC) phosphorylation.[3] # Function Cavin-2 is required for blood vessel formation (angiogenesis) in humans and zebrafish and required also for the endothelial cell proliferation, migration and invasion in humans.[4] Cavin-2 plays an important role in endothelial cell maintenance by regulating eNOS activity.[4] Cavin-2 controls the generation of nitric oxide (NO) in human endothelial cells by controlling the activity and stability of the protein endothelial nitric-oxide synthase (eNOS).[4] # Secretion Cavin-2 is highly secreted from human endothelial cells (HUVEC), they are secreted through endothelial microparticles (EMPs) but not exosomes and is required for EMP biogenesis.[4] # Clinical significance SDPR is shown to act as a metastasis suppressor by xenograft studies utilizing breast cancer cell lines.[5] SDPR may elicit its metastasis suppressor function by directly interacting with ERK and limiting its pro-survival role.[5] Moreover, it is suggested that SDPR is silenced during breast cancer progression by promoter DNA methylation.[5] Metastasis suppressor role of SDPR may go beyond breast cancer since tumor samples from bladder, colorectal, lung, pancreatic, and ovarian cancers as well as sarcomas also exhibited loss of SDPR expression.[5]

https://www.wikidoc.org/index.php/SDPR

b72cbdafd3df19995d52f848ac728ea4e6d557ad

wikidoc

SELT

SELT Selenoprotein T, also known as SELT, is a protein that in humans is encoded by the SELT gene. # Gene The selenocysteine is encoded by the UGA codon that normally signals translation termination. The 3' UTR of selenoprotein genes have a common stem-loop structure, the sec insertion sequence (SECIS), that is necessary for the recognition of UGA as a Sec codon rather than as a stop signal. # Protein structure Selenoprotein T contains a selenocysteine (Sec) residue at its active site.

SELT Selenoprotein T, also known as SELT, is a protein that in humans is encoded by the SELT gene.[1][2][3] # Gene The selenocysteine is encoded by the UGA codon that normally signals translation termination. The 3' UTR of selenoprotein genes have a common stem-loop structure, the sec insertion sequence (SECIS), that is necessary for the recognition of UGA as a Sec codon rather than as a stop signal.[3] # Protein structure Selenoprotein T contains a selenocysteine (Sec) residue at its active site.

https://www.wikidoc.org/index.php/SELT

17144645b157844de16243b750e74ef62b27bcf8

wikidoc

SGCG

SGCG Gamma-sarcoglycan is a protein that in humans is encoded by the SGCG gene. The α to δ-sarcoglycans are expressed predominantly (β) or exclusively (α, γ and δ) in striated muscle. A mutation in any of the sarcoglycan genes may lead to a secondary deficiency of the other sarcoglycan proteins, presumably due to destabilisation of the sarcoglycan complex. The disease-causing mutations in the α to δ genes cause disruptions within the dystrophin-associated protein (DAP) complex in the muscle cell membrane. The transmembrane components of the DAP complex link the cytoskeleton to the extracellular matrix in adult muscle fibres, and are essential for the preservation of the integrity of the muscle cell membrane. # Function Gamma-sarcoglycan is one of several sarcolemmal transmembrane glycoproteins that interact with dystrophin, probably to provide a link between the membrane associated cytoskeleton and the extracellular matrix. Defects in the protein can lead to early onset autosomal recessive muscular dystrophy, in particular limb-girdle muscular dystrophy, type 2C (LGMD2C). # Structure ## Gene Human SGCG gene maps to chromosome 13 at q12, spans over 100 kb of DNA and includes 8 exons. ## Protein Gamma-sarcoglycan is a type II transmembrane protein and consists of 291 amino acids. It has a 35 amino acid intracellular N-terminal region, a 25 amino acid single transmembrane domain, and a 231 amino acid extra-cellular C-terminus. # Clinical significance Sarcoglycanopathies are autosomal recessive limb girdle muscular dystrophies (LGMDs) caused by mutations in any of the four sarcoglycan genes: α (LGMD2D), β (LGMD2E), γ (LGMD2C) and δ (LGMD2F). Severe childhood autosomal recessive muscular dystrophy (SCARMD) is a progressive muscle-wasting disorder that segregates with microsatellite markers at γ-sarcoglycan gene. Mutations in the γ-sarcoglycan gene were first described in the Maghreb countries of North Africa, where γ-sarcoglycanopathy has a higher than usual incidence. One common mutation, Δ-521T, which causes a severe phenotype, occurs both in the Maghreb population and in other countries. A Cys283Tyr mutation has been identified in the Gypsy population causing a severe phenotype and a Leu193Ser mutation which causes a mild phenotype. # Interactions SGCG has been shown to interact with FLNC.

SGCG Gamma-sarcoglycan is a protein that in humans is encoded by the SGCG gene.[1][2] The α to δ-sarcoglycans are expressed predominantly (β) or exclusively (α, γ and δ) in striated muscle.[3] A mutation in any of the sarcoglycan genes may lead to a secondary deficiency of the other sarcoglycan proteins, presumably due to destabilisation of the sarcoglycan complex.[4] The disease-causing mutations in the α to δ genes cause disruptions within the dystrophin-associated protein (DAP) complex in the muscle cell membrane.[5] The transmembrane components of the DAP complex link the cytoskeleton to the extracellular matrix in adult muscle fibres,[6] and are essential for the preservation of the integrity of the muscle cell membrane.[7] # Function Gamma-sarcoglycan is one of several sarcolemmal transmembrane glycoproteins that interact with dystrophin, probably to provide a link between the membrane associated cytoskeleton and the extracellular matrix. Defects in the protein can lead to early onset autosomal recessive muscular dystrophy, in particular limb-girdle muscular dystrophy, type 2C (LGMD2C).[2] # Structure ## Gene Human SGCG gene maps to chromosome 13 at q12, spans over 100 kb of DNA and includes 8 exons.[8] ## Protein Gamma-sarcoglycan is a type II transmembrane protein and consists of 291 amino acids. It has a 35 amino acid intracellular N-terminal region, a 25 amino acid single transmembrane domain, and a 231 amino acid extra-cellular C-terminus.[4] # Clinical significance Sarcoglycanopathies are autosomal recessive limb girdle muscular dystrophies (LGMDs) caused by mutations in any of the four sarcoglycan genes: α (LGMD2D), β (LGMD2E), γ (LGMD2C) and δ (LGMD2F).[3] Severe childhood autosomal recessive muscular dystrophy (SCARMD) is a progressive muscle-wasting disorder that segregates with microsatellite markers at γ-sarcoglycan gene. Mutations in the γ-sarcoglycan gene were first described in the Maghreb countries of North Africa,[9] where γ-sarcoglycanopathy has a higher than usual incidence. One common mutation, Δ-521T, which causes a severe phenotype, occurs both in the Maghreb population and in other countries.[8] A Cys283Tyr mutation has been identified in the Gypsy population causing a severe phenotype and a Leu193Ser mutation which causes a mild phenotype.[1][10] # Interactions SGCG has been shown to interact with FLNC.[11][12]

https://www.wikidoc.org/index.php/SGCG

93c284d697448496a853f51ab0d9973c45ed03c9

wikidoc

SGCZ

SGCZ Sarcoglycan zeta also known as SGCZ is a protein which in humans is encoded by the SGCZ gene. # Function The zeta-sarcoglycan gene measures over 465 kb and localizes to 8p22. This protein is part of the sarcoglycan complex, a group of 6 proteins. The sarcoglycans are all N-glycosylated transmembrane proteins with a short intra-cellular domain, a single transmembrane region and a large extra-cellular domain containing a carboxyl-terminal cluster with several conserved cysteine residues. The sarcoglycan complex is part of the dystrophin-associated glycoprotein complex (DGC), which bridges the inner cytoskeleton and the extracellular matrix. # Clinical significance Zeta-sarcoglycan is reduced in mouse models of muscular dystrophy and SGCZ is found as a component of the vascular smooth muscle sarcoglycan complex. Hence SGCZ may be important in the pathogenesis of muscular dystrophy.

SGCZ Sarcoglycan zeta also known as SGCZ is a protein which in humans is encoded by the SGCZ gene.[1] # Function The zeta-sarcoglycan gene measures over 465 kb and localizes to 8p22. This protein is part of the sarcoglycan complex, a group of 6 proteins. The sarcoglycans are all N-glycosylated transmembrane proteins with a short intra-cellular domain, a single transmembrane region and a large extra-cellular domain containing a carboxyl-terminal cluster with several conserved cysteine residues. The sarcoglycan complex is part of the dystrophin-associated glycoprotein complex (DGC), which bridges the inner cytoskeleton and the extracellular matrix.[2] # Clinical significance Zeta-sarcoglycan is reduced in mouse models of muscular dystrophy and SGCZ is found as a component of the vascular smooth muscle sarcoglycan complex. Hence SGCZ may be important in the pathogenesis of muscular dystrophy.[1]

https://www.wikidoc.org/index.php/SGCZ

762d2ffdd25e031d07dfe14c3a16837ddc51721e

wikidoc

SGEF

SGEF SGEF (Src homology 3 domain-containing Guanine nucleotide Exchange Factor) is a 97 kDa protein involved in intracellular signalling networks. It functions as a guanine nucleotide exchange factor (GEF) for RhoG, a small G protein of the Rho family. # Discovery SGEF was discovered during a screen for androgen-responsive genes in human prostate cancer cells. Subsequent northern blot analysis revealed expression of SGEF in tissues of the heart, brain, placenta, lung, liver, kidney, pancreas, prostate, testis, small intestine and colon. SGEF is also expressed in endothelial cells of the vasculature. Several widely used cell lines express this protein, these include A431, HeLa, HUT78, HEK-293, Jurkat, THP, PC12, RAJI, U937 and Meg-01. SGEF was identified to contribute to the formation of atherosclerosis through promoting endothelial docking structures that resulted in retention of leukocytes at athero-prone sites of inflammation . Genetic variants in SGEF have been associated with coronary artery disease # Structure and Function SGEF is part of a large class of proteins (GEFs) that function to activate small G proteins. In their resting state G proteins are bound to guanosine diphosphate (GDP) and their activation requires the dissociation of GDP and binding of guanosine triphosphate (GTP). GEFs activate G proteins by promoting nucleotide exchange. SGEF has the canonical GEF structure of tandem DH and PH domains, which elicit nucleotide exchange and, in addition, contains an N-terminal proline-rich motif and a C-terminal SH3 domain. Proline regions and SH3 domains often mediate recruitment and binding to adaptor proteins suggesting that SGEF is probably involved in the formation of heteromultimeric protein complexes. # Regulation of SGEF activity Data from several studies suggest that SGEF is regulated by its recruitment to transmembrane receptor-linked adaptor proteins via its SH3 domain. In one study, mutation of the SH3 domain disrupted SGEF-dependent functions in NIH-3T3 fibroblasts. In endothelial cells SGEF was recruited to the intracellular domain of the transmembrane adhesion molecule ICAM-1 upon leukocyte adhesion to the endothelium.

SGEF SGEF (Src homology 3 domain-containing Guanine nucleotide Exchange Factor) is a 97 kDa protein involved in intracellular signalling networks. It functions as a guanine nucleotide exchange factor (GEF) for RhoG, a small G protein of the Rho family.[1] # Discovery SGEF was discovered during a screen for androgen-responsive genes in human prostate cancer cells.[2] Subsequent northern blot analysis revealed expression of SGEF in tissues of the heart, brain, placenta, lung, liver, kidney, pancreas, prostate, testis, small intestine and colon. SGEF is also expressed in endothelial cells of the vasculature.[3] Several widely used cell lines express this protein, these include A431, HeLa, HUT78, HEK-293, Jurkat, THP, PC12, RAJI, U937 and Meg-01.[4] SGEF was identified to contribute to the formation of atherosclerosis through promoting endothelial docking structures that resulted in retention of leukocytes at athero-prone sites of inflammation [5]. Genetic variants in SGEF have been associated with coronary artery disease[6] # Structure and Function SGEF is part of a large class of proteins (GEFs) that function to activate small G proteins. In their resting state G proteins are bound to guanosine diphosphate (GDP) and their activation requires the dissociation of GDP and binding of guanosine triphosphate (GTP). GEFs activate G proteins by promoting nucleotide exchange. SGEF has the canonical GEF structure of tandem DH and PH domains, which elicit nucleotide exchange and, in addition, contains an N-terminal proline-rich motif and a C-terminal SH3 domain.[2] Proline regions and SH3 domains often mediate recruitment and binding to adaptor proteins suggesting that SGEF is probably involved in the formation of heteromultimeric protein complexes. # Regulation of SGEF activity Data from several studies suggest that SGEF is regulated by its recruitment to transmembrane receptor-linked adaptor proteins via its SH3 domain. In one study, mutation of the SH3 domain disrupted SGEF-dependent functions in NIH-3T3 fibroblasts.[4] In endothelial cells SGEF was recruited to the intracellular domain of the transmembrane adhesion molecule ICAM-1 upon leukocyte adhesion to the endothelium.[3]

https://www.wikidoc.org/index.php/SGEF

cc1d16e8ebbe460910da71edfca8a73c5596c425

wikidoc

SGK1

SGK1 Serine/threonine-protein kinase Sgk1 also known as serum and glucocorticoid-regulated kinase 1 is an enzyme that in humans is encoded by the SGK1 gene. SGK1 belongs to a subfamily of serine/threonine kinases that is under acute transcriptional control by several stimuli, including serum and glucocorticoids. The kinase is activated by insulin and growth factors via phosphatidylinositide-3-kinase, phosphoinositide-dependent kinase PDK1 and mammalian target of rapamycin mTORC2. It has been shown to "regulate several enzymes and transcription factors; SGK1 contributes to the regulation of transport, hormone release, neuroexcitability, inflammation, cell proliferation and apoptosis". SGK1 increases the protein abundance and/or activity of a variety of ion channel, carriers, and the Na+/K+-ATPase. Over the past few years, there has been increasing evidence that SGK1 expression is regulated during both discrete developmental stages and pathological conditions such as hypertension, diabetic neuropathy, ischemia, trauma, and neurodegenerative diseases. # Function This gene encodes a serine/threonine protein kinase that plays an important role in cellular stress response. This kinase activates certain potassium, sodium, and chloride channels, suggesting an involvement in the regulation of processes such as cell survival, neuronal excitability, and renal sodium excretion. ## Ion channel and transporter regulation SGK1 has been shown to regulate the following ion channels: - Epithelial Na+ channel ENaC - Renal outer medullary K+ channel ROMK1 - Renal epithelial Ca2+ channel TRPV5 - Ubiquitous Cl− channel ClC2 - Cardiac voltage-gated Na+ channel SCN5A - Cardiac and epithelial K+ channels KCNE1/KCNQ1 - Voltage-gated K+ channels Kv1.3, Kv1.5, and Kv4.3 - Glutamate Receptors The following carriers and pumps are influenced by SGK1: - Glucose Transporters - Creatine Transporter CreaT - Phosphate Carrier ## Regulation of cell volume SGK1 is upregulated by osmotic and isotonic cell shrinkage. "It is tempting to speculate that SGK1-dependent regulation of cation channels contributes to the regulation of cell volume, which involves cation channels in a variety of cells". The entrance of NaCl and osmotically driven water into cells leads to an increase in the cell's regulatory cell volume. This occurs as the entrance of Na+ depolarizes the cell, thus allowing the parallel entrance of Cl−. SGK1 has also been shown to increase the activity of cell volume-regulated Cl− channel ClC2. The activation of these Cl− channels result in the exit of Cl− and eventually the exit of K+, and the cellular loss of KCl results in a decrease of regulatory cell volume. However, the functional significance of SGK1 in cell volume regulation, along with its stimulation of cation channels, is still not clearly understood. "Moreover, the molecular identity of the cation channels and the mechanisms of their regulation by glucocorticoids and osmotic cell shrinkage have remained elusive". The following observations seem to have conflicting results, as one suggests a role of SGK1 by cell shrinkage and regulatory cell volume increase while the other suggests regulatory cell volume decrease. It is possible that SGK1 works to maintain regulatory cell volume by increasing the cell's ability to cope with alterations in cell volume. ### Dehydration The hydration state of the brain is critical to neuronal function. One way hydration modifies cerebral function is by influencing neuronal and glial cell volume. Dehydration alters the expression of a wide variety of genes including SGK1. "It has been shown that SGK1-sensitive functions contribute significantly to the altered function of the dehydrated brain". ## Cell proliferation and apoptosis SGK1 has been shown to inhibit apoptosis. "The antiapoptotic effect of SGK1 and SGK3 has been attributed in part to phosphorylation of forkhead transcription factors". It is suggested that proliferative signals transport SGK1 into the nucleus, and the effect of SGK1 on cell proliferation may be due to its ability to regulate Kv1.3. "The upregulation of Kv1.3 channel activity may be important for the proliferative effect of growth factors, as IGF-I induced cell proliferation is disrupted by several blockers of Kv channels". SGK1 knockout mice show seemingly normal development. "Thus SGK1 is either not a crucial element in the regulation of cell proliferation or apoptosis, or related kinase(s) can effectively replace SGK1 function in the SGK1 knockout mice". ## Memory formation It has been suggested that this kinase plays a critical role in long-term memory formation. Wild-type SGK1 improves the learning abilities of rats. On the other hand, the transfection of inactive SGK1 decreases their abilities in spatial, fear-conditioning, and novel object recognition learning. The effect of glutamate receptors may also impact the role of SGK1 in memory consolidation. "SGK isoforms upregulate AMPA and kainate receptors and thus are expected to enhance the excitatory effects of glutamate". Synaptic transmission and hippocampal plasticity are both affected by kainate receptors. A lack of SGK may reduce glutamate clearance from the synaptic cleft leading to altered function or regulation of glutamate transporters and receptors; This could result in increasing neuroexcitotoxicity and eventually neuronal cell death. ### Long-term potentiation SGK has been to shown to facilitate the expression of long-term potentiation in hippocampal neurons and neuronal plasticity. SGK mRNA expression in the hippocampus in enhanced by the AMPA receptor. Moreover, "AMPA receptor-mediated synaptic transmission is closely associated with the late phase of long-term potentiation". ## Transcription The human isoform of SGK1 has been identified as a cell volume-regulated gene that is transcriptionally upregulated by cell shrinkage. "The regulation of SGK1 transcript levels is fast; appearance and disappearance of SGK1 mRNA require <20 min". Its transcription is increasingly expressed by serum and glucocorticoids, and transcriptional changes in SGK1 expression occur in correlation with the appearance of cell death. Signaling molecules involved in transcriptional regulation of SGK1 include cAMP, p53, and protein kinase C. As SGK1 transcription is sensitive to cell volume, cerebral SGK1 expression is upregulated by dehydration. "SGK1 expression is controlled by a large number of stimuli including serum, IFG-1, oxidative stress, cytokines, hypotonic conditions, and glucocorticoids". Mineralocorticoids, gonadotropins, fibroblast and platelet-derived growth factor, and other cytokines are also understood to stimulate SGK1 transcription. The upregulation of SGK1 in various neurodegenerative diseases correlates directly with these stimuli, as alterations in these stimuli accompany many neurodegenerative diseases. - Glucocorticoids: SGK expression is mainly regulated by glucocorticoids. Glucocorticoids have been shown to enhance memory consolidation in a range of exercises in animals. Glucocorticoid hormones are also consistently increased in patients with severe depression. It has been shown that chronically high concentrations of glucocorticoids impair hippocampal neurogenesis by activating the glucocorticoid receptor (GR). Indeed, "SGK1 is a key enzyme involved in the downstream mechanisms by which glucocorticoids reduce neurogenesis and in the upstream potentiation and maintenance of GR function, even after glucocorticoid withdrawal". - Oxidative Stress: Oxidative stress is a common component of the neurodegenerative process. "It has been shown to induce SGK expression through a p38/MAPK-dependent pathway, with SGK1 responding rapidly and transiently to changes in stress". - DNA Damage: "SGK1 gene transcription is stimulated by DNA damage through p53 and activation of extracellular signal-regulated kinase (ERK1/2)". Other stimuli include neuronal injury, neuronal excitotoxicity, increased cytosolic Ca2+ concentration, ischemia, and nitric oxide. ## Metabolism SGK1, along with SGK3, has been shown to stimulate the absorption of intestinal glucose by the Na+-glucose cotransporter SGLT1. "SGK1 also favors cellular glucose uptake from the circulation into several tissues including brain, fat, and skeletal muscle". SGK1 also plays a critical role in the stimulation of cellular glucose uptake by insulin. Accordingly, SGK1 does not only integrate effects of mineralocorticoids and insulin on renal tubular Na+ transport but similarly affects glucose transport". ## Kidney By aldosterone, insulin, and IFG-I, SGK1 has been suggested to influence the regulation of ENaC and participate in the regulation of renal Na+ excretion. It has been indicated "that activation of ENaC by ADH or insulin depends on SGK1 and/or reflects independent pathways induced by ADH/insulin and SGK1 that converge on the same target structures". Renal ENaC function, along with renal mineralocorticoid action, is also partly dependent upon the presence of SGK1. One study also determined that SGK1 has a critical role in insulin-induced renal Na+ retention. "SGK1 plays at least a dual role in mineralocorticoid-regulated NaCl homeostasis. SGK1 dependence of both NaCl intake and renal NaCl reabsorption suggests that excessive SGK1 activity leads to arterial hypertension by simultaneous stimulation of oral NaCl intake and renal NaCl retention". ## Gastrointestinal Including having a high expression in enterocytes, SGK1 is highly expressed in the gastrointestinal tract. It has been suggested that glucocorticoids are the primary stimulant of intestinal SGK1 expression. Unlike in renal function, ENaC regulation in the colon is currently not fully understood. At the current time, it seems SGK1 is not required for stimulation of ENaC in the distal colon. ## Cardiovascular The heart is among one of the many tissues with high SGK1 expression. As SGK1 affects both Na+ intake and renal+ excretion, the regulation of blood pressure could be influenced by SGK1-induced salt imbalance. Activated SGK1, due to insulin, may lead to Na+ reabsorption and consequently blood pressure. SGK1 has been shown to impact the QT interval of the heart electrical cycle. As the QT interval represents the electrical depolarization and repolarization of the left and right ventricles, "SGK1 may have the capacity to shorten Q-T". "In support of this, a gene variant of SGK1, presumably conferring enhanced SGK1 activity is indeed associated with a shortened Q-T interval in humans". # Clinical significance A gain-of-function mutation in SGK1, or serum and glucocorticoid-inducible kinase 1, can lead to a shortening of the QT interval, which represents the repolarization time of the cardiac cells after a cardiac muscle contraction action potential. SGK1 does this by interacting with the KvLQT1 channel in cardiac cells, stimulating this channel when it is complex with KCNE1. SGK1 stimulates the slow delayed rectifier potassium current through this channel by phosphorylating PIKfyve, which then makes PI(3,5)P2, which goes on to increase the RAB11-dependent insertion of the KvLQT1/KCNE1 channels into the plasma membrane of cardiac neurons. SGK1 phosphorylates PIKfyve, which results in regulated channel activity through RAB11-dependent exocytosis of these KvLQT1/KCNE1-containing vesicles. Stress-induced stimuli have been known to activate SGK1, which demonstrates how Long QT Syndrome is brought on by stressors to the body or to the heart itself. By increasing the insertion of KVLQT1/KCNE1 channels into the plasma membrane through an alteration of trafficking within the cell, SGK1 is able to enhance the slow delayed potassium rectifier current in the neurons. ## Role in neuronal disease Two majors components of SGK1 expression, oxidative stress and an increase in glucocorticoids, are common components of the neurodegenerative process. "Studies suggest that SGK1 is an important player in cell death processes underlying neurodegerative diseases, and its role seems to be neuroprotective". AMPA and Kainate receptors are regulated by SGK isoforms. AMPA receptor activation is key for ischemic-induced cell death. Where changes in GluR2 levels are observed, "it has been suggested that disturbed SGK1-dependent regulation of AMPA and kainate receptors could participate in the pathophysiology of Amyotrophic lateral sclerosis (ALS), schizophrenia, and epilepsy". Kainate receptors are thought to be involved in epileptic activity. Glutamate transporters act to remove glutamate from extracellular space. A lack of SGK1 may prevent glutamate activity while at the same time decreasing glutamate clearance from the synaptic cleft. "As glutamate may exert neurotoxic effects, altered function or regulation of glutamate transporters and glutamate receptors may foster neuroexcitotoxicity". ### Huntingtin Counteracting huntingtin toxicity, SGK1 has been found to phosphorylate huntingtin. "Genomic upregulation of SGK1 coincides with the onset of dopaminergic cell death in a model of Parkinson's disease". However, at the current time, it is unclear whether SGK1 prevents or motivates cell death. An excessive expression of SGK1 has also been observed in Rett syndrome (RTT), which is a disorder of severe mental retardation. SGK1 is suggested to take part in the signaling of brain-derived neurotrophic factor (BDNF). It is known that BDNF is involved in neuronal survival, plasticity, mood, and long-term memory. "SGK1 could participate in the signaling of BDNF during schizophrenia, depression, and Alzheimer's disease". "Moreover, BDNF concentrations are modified after major psychiatric treatment strategies", including antidepressants and electroconvulsive therapy. ### Other neuronal diseases - Tau protein: Tau protein is phosphorylated by SGK1. SGK1 may contribute to Alzheimer's Disease, as it is paralleled by hyperphosphorylation of tau. - CreaT: "The ability of SGK1 to upregulate the creatine transporter CreaT may similarly be of pathological significance, as individuals with defective CreaT have been shown to suffer from mental retardation". - SKG1 mRNA: As SGK1 deficiency is simultaneously paired with insufficient glucocorticoid signaling, it has been suggested that it may participate in major depressive disorder. "A study looking at SGK1 mRNA expression in depressed patients found that depressed patients had significantly higher SGK1 mRNA levels". # Interactions SGK has been shown to interact with: - KPNA2, - MAPK7, - NEDD4, - PDPK1, and - SLC9A3R2.

SGK1 Serine/threonine-protein kinase Sgk1 also known as serum and glucocorticoid-regulated kinase 1 is an enzyme that in humans is encoded by the SGK1 gene. SGK1 belongs to a subfamily of serine/threonine kinases that is under acute transcriptional control by several stimuli, including serum and glucocorticoids. The kinase is activated by insulin and growth factors via phosphatidylinositide-3-kinase, phosphoinositide-dependent kinase PDK1 and mammalian target of rapamycin mTORC2.[1][2] It has been shown to "regulate several enzymes and transcription factors; SGK1 contributes to the regulation of transport, hormone release, neuroexcitability, inflammation, cell proliferation and apoptosis".[1][2] SGK1 increases the protein abundance and/or activity of a variety of ion channel, carriers, and the Na+/K+-ATPase. Over the past few years, there has been increasing evidence that SGK1 expression is regulated during both discrete developmental stages and pathological conditions such as hypertension, diabetic neuropathy, ischemia, trauma, and neurodegenerative diseases.[3] # Function This gene encodes a serine/threonine protein kinase that plays an important role in cellular stress response. This kinase activates certain potassium, sodium, and chloride channels, suggesting an involvement in the regulation of processes such as cell survival, neuronal excitability, and renal sodium excretion. ## Ion channel and transporter regulation SGK1 has been shown to regulate the following ion channels: - Epithelial Na+ channel ENaC[4][5] - Renal outer medullary K+ channel ROMK1 [2][6] - Renal epithelial Ca2+ channel TRPV5 [2][7][8] - Ubiquitous Cl− channel ClC2 [2][9] - Cardiac voltage-gated Na+ channel SCN5A [10][11] - Cardiac and epithelial K+ channels KCNE1/KCNQ1 [11][12] - Voltage-gated K+ channels Kv1.3, Kv1.5, and Kv4.3 [11][13] - Glutamate Receptors [2][14] The following carriers and pumps are influenced by SGK1: - Glucose Transporters[15] - Creatine Transporter CreaT[16] - Phosphate Carrier[9] ## Regulation of cell volume SGK1 is upregulated by osmotic and isotonic cell shrinkage. "It is tempting to speculate that SGK1-dependent regulation of cation channels contributes to the regulation of cell volume, which involves cation channels in a variety of cells".[17] The entrance of NaCl and osmotically driven water into cells leads to an increase in the cell's regulatory cell volume. This occurs as the entrance of Na+ depolarizes the cell, thus allowing the parallel entrance of Cl−. SGK1 has also been shown to increase the activity of cell volume-regulated Cl− channel ClC2.[9] The activation of these Cl− channels result in the exit of Cl− and eventually the exit of K+, and the cellular loss of KCl results in a decrease of regulatory cell volume. However, the functional significance of SGK1 in cell volume regulation, along with its stimulation of cation channels, is still not clearly understood. "Moreover, the molecular identity of the cation channels and the mechanisms of their regulation by glucocorticoids and osmotic cell shrinkage have remained elusive".[17] The following observations seem to have conflicting results, as one suggests a role of SGK1 by cell shrinkage and regulatory cell volume increase [18] while the other suggests regulatory cell volume decrease. It is possible that SGK1 works to maintain regulatory cell volume by increasing the cell's ability to cope with alterations in cell volume.[2][17] ### Dehydration The hydration state of the brain is critical to neuronal function. One way hydration modifies cerebral function is by influencing neuronal and glial cell volume. Dehydration alters the expression of a wide variety of genes including SGK1. "It has been shown that SGK1-sensitive functions contribute significantly to the altered function of the dehydrated brain".[1] ## Cell proliferation and apoptosis SGK1 has been shown to inhibit apoptosis. "The antiapoptotic effect of SGK1 and SGK3 has been attributed in part to phosphorylation of forkhead transcription factors".[1] It is suggested that proliferative signals transport SGK1 into the nucleus, and the effect of SGK1 on cell proliferation may be due to its ability to regulate Kv1.3.[1][11][13] "The upregulation of Kv1.3 channel activity may be important for the proliferative effect of growth factors, as IGF-I induced cell proliferation is disrupted by several blockers of Kv channels".[13] SGK1 knockout mice show seemingly normal development.[19] "Thus SGK1 is either not a crucial element in the regulation of cell proliferation or apoptosis, or related kinase(s) can effectively replace SGK1 function in the SGK1 knockout mice".[1] ## Memory formation It has been suggested that this kinase plays a critical role in long-term memory formation.[20] Wild-type SGK1 improves the learning abilities of rats. On the other hand, the transfection of inactive SGK1 decreases their abilities in spatial, fear-conditioning, and novel object recognition learning.[1][2] The effect of glutamate receptors may also impact the role of SGK1 in memory consolidation. "SGK isoforms upregulate AMPA and kainate receptors and thus are expected to enhance the excitatory effects of glutamate".[1] Synaptic transmission and hippocampal plasticity are both affected by kainate receptors. A lack of SGK may reduce glutamate clearance from the synaptic cleft leading to altered function or regulation of glutamate transporters and receptors; This could result in increasing neuroexcitotoxicity and eventually neuronal cell death.[1][2][17] ### Long-term potentiation SGK has been to shown to facilitate the expression of long-term potentiation in hippocampal neurons and neuronal plasticity. SGK mRNA expression in the hippocampus in enhanced by the AMPA receptor. Moreover, "AMPA receptor-mediated synaptic transmission is closely associated with the late phase of long-term potentiation".[20] ## Transcription The human isoform of SGK1 has been identified as a cell volume-regulated gene that is transcriptionally upregulated by cell shrinkage. "The regulation of SGK1 transcript levels is fast; appearance and disappearance of SGK1 mRNA require <20 min".[18] Its transcription is increasingly expressed by serum and glucocorticoids, and transcriptional changes in SGK1 expression occur in correlation with the appearance of cell death.[3] Signaling molecules involved in transcriptional regulation of SGK1 include cAMP, p53, and protein kinase C. As SGK1 transcription is sensitive to cell volume, cerebral SGK1 expression is upregulated by dehydration. "SGK1 expression is controlled by a large number of stimuli including serum, IFG-1, oxidative stress, cytokines, hypotonic conditions, and glucocorticoids".[3] Mineralocorticoids, gonadotropins, fibroblast and platelet-derived growth factor, and other cytokines are also understood to stimulate SGK1 transcription.[11][17] The upregulation of SGK1 in various neurodegenerative diseases correlates directly with these stimuli, as alterations in these stimuli accompany many neurodegenerative diseases. - Glucocorticoids: SGK expression is mainly regulated by glucocorticoids.[20] Glucocorticoids have been shown to enhance memory consolidation in a range of exercises in animals. Glucocorticoid hormones are also consistently increased in patients with severe depression. It has been shown that chronically high concentrations of glucocorticoids impair hippocampal neurogenesis by activating the glucocorticoid receptor (GR). Indeed, "SGK1 is a key enzyme involved in the downstream mechanisms by which glucocorticoids reduce neurogenesis and in the upstream potentiation and maintenance of GR function, even after glucocorticoid withdrawal".[21] - Oxidative Stress: Oxidative stress is a common component of the neurodegenerative process. "It has been shown to induce SGK expression through a p38/MAPK-dependent pathway, with SGK1 responding rapidly and transiently to changes in stress".[22] - DNA Damage: "SGK1 gene transcription is stimulated by DNA damage through p53 and activation of extracellular signal-regulated kinase (ERK1/2)".[11][17] Other stimuli include neuronal injury, neuronal excitotoxicity, increased cytosolic Ca2+ concentration, ischemia, and nitric oxide. ## Metabolism SGK1, along with SGK3, has been shown to stimulate the absorption of intestinal glucose by the Na+-glucose cotransporter SGLT1. "SGK1 also favors cellular glucose uptake from the circulation into several tissues including brain, fat, and skeletal muscle".[15] SGK1 also plays a critical role in the stimulation of cellular glucose uptake by insulin. Accordingly, SGK1 does not only integrate effects of mineralocorticoids and insulin on renal tubular Na+ transport but similarly affects glucose transport".[17] ## Kidney By aldosterone, insulin, and IFG-I, SGK1 has been suggested to influence the regulation of ENaC and participate in the regulation of renal Na+ excretion.[23][24] It has been indicated "that activation of ENaC by ADH or insulin depends on SGK1 and/or reflects independent pathways induced by ADH/insulin and SGK1 that converge on the same target structures".[17] Renal ENaC function, along with renal mineralocorticoid action, is also partly dependent upon the presence of SGK1. One study also determined that SGK1 has a critical role in insulin-induced renal Na+ retention.[25] "SGK1 plays at least a dual role in mineralocorticoid-regulated NaCl homeostasis. SGK1 dependence of both NaCl intake and renal NaCl reabsorption suggests that excessive SGK1 activity leads to arterial hypertension by simultaneous stimulation of oral NaCl intake and renal NaCl retention".[17] ## Gastrointestinal Including having a high expression in enterocytes, SGK1 is highly expressed in the gastrointestinal tract.[17][26] It has been suggested that glucocorticoids are the primary stimulant of intestinal SGK1 expression. Unlike in renal function, ENaC regulation in the colon is currently not fully understood. At the current time, it seems SGK1 is not required for stimulation of ENaC in the distal colon.[17] ## Cardiovascular The heart is among one of the many tissues with high SGK1 expression. As SGK1 affects both Na+ intake and renal+ excretion, the regulation of blood pressure could be influenced by SGK1-induced salt imbalance. Activated SGK1, due to insulin, may lead to Na+ reabsorption and consequently blood pressure.[17][27] SGK1 has been shown to impact the QT interval of the heart electrical cycle. As the QT interval represents the electrical depolarization and repolarization of the left and right ventricles, "SGK1 may have the capacity to shorten Q-T".[17] "In support of this, a gene variant of SGK1, presumably conferring enhanced SGK1 activity is indeed associated with a shortened Q-T interval in humans".[28] # Clinical significance A gain-of-function mutation in SGK1, or serum and glucocorticoid-inducible kinase 1, can lead to a shortening of the QT interval, which represents the repolarization time of the cardiac cells after a cardiac muscle contraction action potential.[29] SGK1 does this by interacting with the KvLQT1 channel in cardiac cells, stimulating this channel when it is complex with KCNE1. SGK1 stimulates the slow delayed rectifier potassium current through this channel by phosphorylating PIKfyve, which then makes PI(3,5)P2, which goes on to increase the RAB11-dependent insertion of the KvLQT1/KCNE1 channels into the plasma membrane of cardiac neurons.[30] SGK1 phosphorylates PIKfyve, which results in regulated channel activity through RAB11-dependent exocytosis of these KvLQT1/KCNE1-containing vesicles. Stress-induced stimuli have been known to activate SGK1, which demonstrates how Long QT Syndrome is brought on by stressors to the body or to the heart itself. By increasing the insertion of KVLQT1/KCNE1 channels into the plasma membrane through an alteration of trafficking within the cell, SGK1 is able to enhance the slow delayed potassium rectifier current in the neurons.[29] ## Role in neuronal disease Two majors components of SGK1 expression, oxidative stress and an increase in glucocorticoids, are common components of the neurodegenerative process. "Studies suggest that SGK1 is an important player in cell death processes underlying neurodegerative diseases, and its role seems to be neuroprotective".[3] AMPA and Kainate receptors are regulated by SGK isoforms.[14] AMPA receptor activation is key for ischemic-induced cell death.[31] Where changes in GluR2 levels are observed, "it has been suggested that disturbed SGK1-dependent regulation of AMPA and kainate receptors could participate in the pathophysiology of Amyotrophic lateral sclerosis (ALS), schizophrenia, and epilepsy".[1] Kainate receptors are thought to be involved in epileptic activity.[17] Glutamate transporters act to remove glutamate from extracellular space. A lack of SGK1 may prevent glutamate activity while at the same time decreasing glutamate clearance from the synaptic cleft.[14] "As glutamate may exert neurotoxic effects, altered function or regulation of glutamate transporters and glutamate receptors may foster neuroexcitotoxicity".[17] ### Huntingtin Counteracting huntingtin toxicity, SGK1 has been found to phosphorylate huntingtin.[32] "Genomic upregulation of SGK1 coincides with the onset of dopaminergic cell death in a model of Parkinson's disease".[17][33] However, at the current time, it is unclear whether SGK1 prevents or motivates cell death. An excessive expression of SGK1 has also been observed in Rett syndrome (RTT), which is a disorder of severe mental retardation.[34] SGK1 is suggested to take part in the signaling of brain-derived neurotrophic factor (BDNF). It is known that BDNF is involved in neuronal survival, plasticity, mood, and long-term memory. "SGK1 could participate in the signaling of BDNF during schizophrenia, depression, and Alzheimer's disease".[1] "Moreover, BDNF concentrations are modified after major psychiatric treatment strategies",[17] including antidepressants and electroconvulsive therapy. ### Other neuronal diseases - Tau protein: Tau protein is phosphorylated by SGK1. SGK1 may contribute to Alzheimer's Disease, as it is paralleled by hyperphosphorylation of tau.[17] - CreaT: "The ability of SGK1 to upregulate the creatine transporter CreaT may similarly be of pathological significance, as individuals with defective CreaT have been shown to suffer from mental retardation".[16][17] - SKG1 mRNA: As SGK1 deficiency is simultaneously paired with insufficient glucocorticoid signaling, it has been suggested that it may participate in major depressive disorder. "A study looking at SGK1 mRNA expression in depressed patients found that depressed patients had significantly higher SGK1 mRNA levels".[21] # Interactions SGK has been shown to interact with: - KPNA2,[35] - MAPK7,[36] - NEDD4,[37][38] - PDPK1,[39][40] and - SLC9A3R2.[39][41]

https://www.wikidoc.org/index.php/SGK1

b60f4156520d91446ead01b52c5b333ee4925446

wikidoc

SGK3

SGK3 Serine/threonine-protein kinase Sgk3 is an enzyme that in humans is encoded by the SGK3 gene. # Function This gene is a member of the serine/threonine protein kinase family and encodes a phosphoprotein with a PX (phox homology) domain. The protein phosphorylates several target proteins and has a role in neutral amino acid transport and activation of potassium and chloride channels. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. In melanocytic cells SGK3 gene expression may be regulated by MITF. # Interactions SGK3 has been shown to interact with GSK3B.

SGK3 Serine/threonine-protein kinase Sgk3 is an enzyme that in humans is encoded by the SGK3 gene.[1][2][3] # Function This gene is a member of the serine/threonine protein kinase family and encodes a phosphoprotein with a PX (phox homology) domain. The protein phosphorylates several target proteins and has a role in neutral amino acid transport and activation of potassium and chloride channels. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.[3] In melanocytic cells SGK3 gene expression may be regulated by MITF.[4] # Interactions SGK3 has been shown to interact with GSK3B.[5]

https://www.wikidoc.org/index.php/SGK3

4283baa64851b163d4d8b6740a3ce41707fc5836

wikidoc

SHC1

SHC1 SHC-transforming protein 1 is a protein that in humans is encoded by the SHC1 gene. SHC has been found to be important in the regulation of apoptosis and drug resistance in mammalian cells. SCOP classifies the 3D structure as belonging to the SH2 domain family. # Gene and expression The gene SHC1 is located on chromosome 1 and encodes 3 main protein isoforms: p66SHC, p52SHC and p46SHC. These proteins differ in activity and subcellular locations, p66 is the longest and while the p52 and p46 link activated receptor tyrosine kinase to the RAS pathway. The protein SHC1 also acts as a scaffold protein which is used in cell surface receptors. The three proteins that SHC1 codes for have distinctly different molecular weights. All three SHC1 proteins share the same domain arrangement consisting of an N-terminal phosphotyrosine-binding(PTB) domain and a C-terminal Src-homology2(SH2) domain. Both of the domains for the three proteins can bind to tyrosine-phosphorylated proteins but they are different in their phosphopeptide-binding specificities. P66SHC is characterized by having an additional N-terminal CH2 domain. # Function Overexpression of SHC proteins are associated with cancer mitogenesis, carcinogenesis and metastasis. The SHC and its adaptor proteins transmit signaling of the cell surface receptors such as EGFR, erbV-2 and insulin receptors. p52SHC and p46SHC activate the Ras-ERK pathway. p66SHC inhibits ERK1/2 activity and antagonize mitogenic and survival abilities of T-lymphoma Jurkat cell lines. A rise in p66SHC promotes stress induced apoptosis. p66SHC functionally is also involved in regulating oxidative and stress- induced apoptosis – mediating steroid action through the redox signaling pathway. P52SHC and p66SHC have been found in steroid hormone-regulated cancer and metastasizes. ## EGFR pathway SHC1 has been found to act in signaling information after epidermal growth factor(EGF) stimulation. Activated tyrosine kinase receptors, on the cell surface, use proteins such as SHC1 that contain phosphotyrosine binding domains. After the EGF stimulation SHC1 binds to groups of proteins that activate survival pathways. This activation is followed by a sub-network of proteins that bind to SHC1 and are involved cytoskeleton reorganization, trafficking and signal termination. PTPN122 then acts as a switch to convert SHC1 to SgK269-mediated pathways that regulate cell invasion and morphogenesis. SHC1 is not a static scaffold protein, a protein that does not move or change over time, it is dynamic as the conformation changes and modifies the EGFR signaling output over time. ## MCT-1 regulation SHC proteins are differentially regulated by the Multiple Copies in T-cell malignancy(MCT-1). This regulation affects the SHC-Ras-ERK pathway. With MCT-1 reduction the phosphor activation of Ras, MEK and ERk ½ were also reduced, this reduction in ERK also affects cyclin D1. The expression of the SHC proteins (all three) were also dramatically reduced with the reduction of MCT-1 because of this it is thought that MCT-1 acts as an inducer of SHC gene transcription. p66SHC is found to be the protein that is most affected by MCT-1. SHC expression downregulated in tumorigenic processes are identified after MCT-1 depletion. By blocking the MCT-1 activity this could inhibit the SHC signaling cascase and the oncogenicty and tumorigenicity that is regulated by SHC expression. ## Oxidative stress Oxidative stress occurs when the production of reactive oxygen species (ROS) is greater than their catabolism. ROS production by the mitochondria is regulated by many diverse factors including SHC1. The SHC proteins are regulated by tyrosine phosphorylation and are part of the growth factor and stress-induced ERK activation. There have been findings that suggest a correlation between life span and the oxidative stress response. Selective resistance to oxidative stress and extended life span have been related to p66SHC. ## Life span There is a link between oxidative stress, life span and p66SHC in mice because of this relationship the SHC gene has been related to longevity and increasing the life span of the mouse. It has been proposed that SHC1 modulates the life span and stress response through the DAF-2 insulin- like receptor of the IIS pathway. The SHC-1 can directly interact with the DAF-2 in vitro. ## p66SHC metabolism p66SHC operates as a redox enzyme linked to apoptotic cell death. p66SHC has been related to the sirtuin-1 system and has been associated with endothelial damage and repair. This relationships is also related to vascular homeostasis and oxidative stress. p66SHC can be altered by changes in the glucose metabolism and vascular senescence. When protein kinase C is induced by hyperglycemia, p66SCH is induced which then leads to oxidative stress. When the coagulated protease-activated protein C inhibits p66SHC a cytoprotective effect on diabetic nephropathy is placed on the kidneys . When a mutations such as a p66SHC deletion occurs the cardiomyocyte death is reduced and a pool of cardiac stem cells are preserved from oxidative damage – preventing diabetic cardiomyopathy. The deletion of p66SHC also protects from ischemia/reperfusion brain injuries through blunted production of free radicals. # Clinical significance The signaling activation of SHC is implicated in tumorigenic in cancer cells there is a potential to use SHC as a prognostic marker when targeting cancer treatment. SHC1 interacts with SgK269 which is a member of the Src kinase signaling network that characterized basal breast cancer cells. When SgK269 is overexpressed in mammary epithelial cells it promotes the cell growth and might contribute to the progression of aggressive breast cancers. In prostate and ovarian cancer, increased expression of p66Shc appears to promote cell proliferation. and tumorigenicity, particularly in prostate cancer xenografts This tumorigenic effect is related to its ability to increase redox stress in these cancer cells.

SHC1 SHC-transforming protein 1 is a protein that in humans is encoded by the SHC1 gene.[1] SHC has been found to be important in the regulation of apoptosis and drug resistance in mammalian cells. SCOP classifies the 3D structure as belonging to the SH2 domain family. # Gene and expression The gene SHC1 is located on chromosome 1 and encodes 3 main protein isoforms: p66SHC, p52SHC and p46SHC. These proteins differ in activity and subcellular locations, p66 is the longest and while the p52 and p46 link activated receptor tyrosine kinase to the RAS pathway.[2] The protein SHC1 also acts as a scaffold protein which is used in cell surface receptors.[3] The three proteins that SHC1 codes for have distinctly different molecular weights.[4] All three SHC1 proteins share the same domain arrangement consisting of an N-terminal phosphotyrosine-binding(PTB) domain and a C-terminal Src-homology2(SH2) domain. Both of the domains for the three proteins can bind to tyrosine-phosphorylated proteins but they are different in their phosphopeptide-binding specificities.[5] P66SHC is characterized by having an additional N-terminal CH2 domain.[5] # Function Overexpression of SHC proteins are associated with cancer mitogenesis, carcinogenesis and metastasis.[4] The SHC and its adaptor proteins transmit signaling of the cell surface receptors such as EGFR, erbV-2 and insulin receptors. p52SHC and p46SHC activate the Ras-ERK pathway. p66SHC inhibits ERK1/2 activity and antagonize mitogenic and survival abilities of T-lymphoma Jurkat cell lines.[4] A rise in p66SHC promotes stress induced apoptosis.[4] p66SHC functionally is also involved in regulating oxidative and stress- induced apoptosis – mediating steroid action through the redox signaling pathway. P52SHC and p66SHC have been found in steroid hormone-regulated cancer and metastasizes.[4] ## EGFR pathway SHC1 has been found to act in signaling information after epidermal growth factor(EGF) stimulation. Activated tyrosine kinase receptors, on the cell surface, use proteins such as SHC1 that contain phosphotyrosine binding domains. After the EGF stimulation SHC1 binds to groups of proteins that activate survival pathways. This activation is followed by a sub-network of proteins that bind to SHC1 and are involved cytoskeleton reorganization, trafficking and signal termination. PTPN122 then acts as a switch to convert SHC1 to SgK269-mediated pathways that regulate cell invasion and morphogenesis.[3] SHC1 is not a static scaffold protein, a protein that does not move or change over time, it is dynamic as the conformation changes and modifies the EGFR signaling output over time.[6] ## MCT-1 regulation SHC proteins are differentially regulated by the Multiple Copies in T-cell malignancy(MCT-1). This regulation affects the SHC-Ras-ERK pathway.[4] With MCT-1 reduction the phosphor activation of Ras, MEK and ERk ½ were also reduced, this reduction in ERK also affects cyclin D1. The expression of the SHC proteins (all three) were also dramatically reduced with the reduction of MCT-1 because of this it is thought that MCT-1 acts as an inducer of SHC gene transcription. p66SHC is found to be the protein that is most affected by MCT-1. SHC expression downregulated in tumorigenic processes are identified after MCT-1 depletion. By blocking the MCT-1 activity this could inhibit the SHC signaling cascase and the oncogenicty and tumorigenicity that is regulated by SHC expression.[4] ## Oxidative stress Oxidative stress occurs when the production of reactive oxygen species (ROS) is greater than their catabolism. ROS production by the mitochondria is regulated by many diverse factors including SHC1.[7] The SHC proteins are regulated by tyrosine phosphorylation and are part of the growth factor and stress-induced ERK activation. There have been findings that suggest a correlation between life span and the oxidative stress response. Selective resistance to oxidative stress and extended life span have been related to p66SHC.[8] ## Life span There is a link between oxidative stress, life span and p66SHC[8] in mice because of this relationship the SHC gene has been related to longevity and increasing the life span of the mouse.[9] It has been proposed that SHC1 modulates the life span and stress response through the DAF-2 insulin- like receptor of the IIS pathway. The SHC-1 can directly interact with the DAF-2 in vitro.[5] ## p66SHC metabolism p66SHC operates as a redox enzyme linked to apoptotic cell death. p66SHC has been related to the sirtuin-1 system and has been associated with endothelial damage and repair. This relationships is also related to vascular homeostasis and oxidative stress.[10] p66SHC can be altered by changes in the glucose metabolism and vascular senescence. When protein kinase C is induced by hyperglycemia, p66SCH is induced which then leads to oxidative stress. When the coagulated protease-activated protein C inhibits p66SHC a cytoprotective effect on diabetic nephropathy is placed on the kidneys . When a mutations such as a p66SHC deletion occurs the cardiomyocyte death is reduced and a pool of cardiac stem cells are preserved from oxidative damage – preventing diabetic cardiomyopathy. The deletion of p66SHC also protects from ischemia/reperfusion brain injuries through blunted production of free radicals.[10] # Clinical significance The signaling activation of SHC is implicated in tumorigenic in cancer cells there is a potential to use SHC as a prognostic marker when targeting cancer treatment.[4] SHC1 interacts with SgK269 which is a member of the Src kinase signaling network that characterized basal breast cancer cells. When SgK269 is overexpressed in mammary epithelial cells it promotes the cell growth and might contribute to the progression of aggressive breast cancers.[11] In prostate and ovarian cancer, increased expression of p66Shc appears to promote cell proliferation.[12] and tumorigenicity, particularly in prostate cancer xenografts[13] This tumorigenic effect is related to its ability to increase redox stress in these cancer cells.[14]

https://www.wikidoc.org/index.php/SHC1

f6605b896037f9d19134af25d63777de7c5c33ef

wikidoc

SIM1

SIM1 Single-minded homolog 1 also known as class E basic helix-loop-helix protein 14 (bHLHe14) is a protein that in humans is encoded by the SIM1 gene. # Function SIM1 and SIM2 genes are homologs of Drosophila melanogaster single-minded (sim), so named because cells in the midline of the sim mutant embryo fail to properly develop and eventually die, and thus the paired longitudinal axon bundles that span the anterior-posterior axis of the embryo (analogous to the embryo's spinal cord) are collapsed into a "single" rudimentary axon bundle at the midline. Sim is a basic helix-loop-helix-PAS domain transcription factor that regulates gene expression in the midline cells. Since the sim gene plays an important role in Drosophila development and has peak levels of expression during the period of neurogenesis, it was proposed that the human SIM2 gene, which resides in a critical region of chromosome 21, is a candidate for involvement in certain dysmorphic features (particularly facial and skull characteristics), abnormalities of brain development, and/or mental retardation of Down syndrome. # Clinical significance Haploinsufficiency of SIM1 has been shown to cause severe early-onset obesity in a human girl with a de novo balanced translocation between chromosomes 1p22.1 and 6q16.2 and has been suggested to cause a Prader-Willi-like phenotype in other cases. Additionally, studies in mice have shown that haploinsufficieny of Sim1 causes obesity that is due to hyperphagia and do not respond properly to increased dietary fat. Overexpression of SIM1 protects against diet induced obesity and rescues the hyperphagia of agouti yellow mice, who have disrupted melanocortin signaling. The obesity and hyperphagia may be mediated by impaired melanocortin activation of PVN neurons and oxytocin deficiency in these mice. It has been demonstrated that modulating Sim1 levels postnatally also leads to hyperphagia and obesity, suggesting a physiological role for Sim1 separate from its role in development. # Interactions SIM1 has been shown to interact with Aryl hydrocarbon receptor nuclear translocator.

SIM1 Single-minded homolog 1 also known as class E basic helix-loop-helix protein 14 (bHLHe14) is a protein that in humans is encoded by the SIM1 gene.[1][2][3] # Function SIM1 and SIM2 genes are homologs of Drosophila melanogaster single-minded (sim), so named because cells in the midline of the sim mutant embryo fail to properly develop and eventually die, and thus the paired longitudinal axon bundles that span the anterior-posterior axis of the embryo (analogous to the embryo's spinal cord) are collapsed into a "single" rudimentary axon bundle at the midline. Sim is a basic helix-loop-helix-PAS domain transcription factor that regulates gene expression in the midline cells. Since the sim gene plays an important role in Drosophila development and has peak levels of expression during the period of neurogenesis, it was proposed that the human SIM2 gene, which resides in a critical region of chromosome 21, is a candidate for involvement in certain dysmorphic features (particularly facial and skull characteristics), abnormalities of brain development, and/or mental retardation of Down syndrome.[3] # Clinical significance Haploinsufficiency of SIM1 has been shown to cause severe early-onset obesity in a human girl with a de novo balanced translocation between chromosomes 1p22.1 and 6q16.2 [4] and has been suggested to cause a Prader-Willi-like phenotype in other cases.[5] Additionally, studies in mice have shown that haploinsufficieny of Sim1 causes obesity that is due to hyperphagia and do not respond properly to increased dietary fat.[2][6] Overexpression of SIM1 protects against diet induced obesity and rescues the hyperphagia of agouti yellow mice,[7] who have disrupted melanocortin signaling. The obesity and hyperphagia may be mediated by impaired melanocortin activation of PVN neurons [8] and oxytocin deficiency in these mice.[9] It has been demonstrated that modulating Sim1 levels postnatally also leads to hyperphagia and obesity,[10][11] suggesting a physiological role for Sim1 separate from its role in development. # Interactions SIM1 has been shown to interact with Aryl hydrocarbon receptor nuclear translocator.[12][13]

https://www.wikidoc.org/index.php/SIM1

fd14f64b28194fe4a4ebaa5b0802305842d09b31

wikidoc

SIM2

SIM2 Single-minded homolog 2 is a protein that in humans is encoded by the SIM2 gene. It plays a major role in the development of the central nervous system midline as well as the construction of the face and head. # Function SIM1 and SIM2 genes are Drosophila single-minded (sim) gene homologs. The Drosophila sim gene encodes a transcription factor that is a master regulator of neurogenesis of midline cells in the central nervous system. SIM2 maps within the so-called Down syndrome chromosomal region, specifically on the q arm of chromosome 21, band 22.2. Based on the mapping position, its potential function as transcriptional repressor and similarity to Drosophila sim, it is proposed that SIM2 may contribute to some specific Down syndrome phenotypes # Interactions SIM2 has been shown to interact with Aryl hydrocarbon receptor nuclear translocator. When the SIM2 gene is tranfected into PC12 cells, it effects the normal cycle of cell maturation. SIM2 inhibits the expression of cyclin E, which in turn inhibits the cell's ability to pass through the G1/S checkpoint and suppresses the cell's proliferation ability. it also up-regulates the presence of p27, a growth inhibitor protein. The presence of p27 inhibits the activation of cell cycle regulatory kinases. # Disease state There are three states of the gene: +/+, +/-, and -/-. When the gene is expressed as SIM2 -/-, it is considered disrupted and many physical malformations are seen, particularly in the craniofacial area. Individuals with SIM2 -/- have either a full or partial secondary palate cleft and malformations in the tongue and pterygoid processes of the sphenoid bone. These malformations cause aerophagia, or the swallowing of air, and postnatal death. Severe aerophagia leads to accumulation of air in the gastrointestinal tract, causing the belly to be distended. It is thought that the over-expression of the SIM2 gene brings about some of the phenotypic deformities that are characteristic of Down syndrome. The presence of SIM2 mRNA in many parts of the brain known to show deformities in individuals with Down syndrome, as well as in the palate, oral and tongue epithelia, mandibular and hyoid bones. # SIM2 Short (SIM2s) There are two known isoforms of SIM2 which play different roles in various tissues. The isoform SIM2 Short (SIM2s) has been shown to be specifically expressed in mammary gland tissue. SIM2s is a splice variant which lacks exon 11 of SIM2. It has been researched that SIM2s acts in mammary gland development and has tumor suppressive characteristics specifically in breast cancer. In a mouse specimen, when SIM2s was not expressed in mammary epithelial cells there were development defects leading to cancer-like characteristics in the cells. The defects were increased cell proliferation, cellular invasion of local stroma, loss of cellular polarity, and loss of E-cadherin cellular adhesion molecules. These observations suggest that SIM2s is essential for proper mammary gland development. Experiments reintroducing SIM2s in human breast cancer cells allowed for the tumor suppressive characteristics to be observed. Comparing normal human breast cells to human breast cancer cells with immunohistochemical staining showed that SIM2s was expressed more in the normal than the cancerous. Reintroducing SIM2s expression in breast cancer cells showed a decrease in growth, proliferation, and invasiveness. SIM2s represses the actions of the matrix metalloprotease-3 gene (MMP3) which include cell migration, cancer progression, and epithelial to mesenchymal transitions (EMT). SIM2s also represses the SLUG transcription factor which in turn suppresses EMT. EMT suppression allows for E-cadherin to remain and for the cell to not undergo pathological EMT associated with tumor formation. These actions show the tumor suppressive effects of SIM2s in mammary epithelium. # Knockout model Scientists can purposefully "knockout" or cause the gene to be disrupted. To do this, they perform homologous recombination and eliminate the predicted start codon and the following 47 amino acids. Then the EcoRI restriction site is introduced into the chromosome.

SIM2 Single-minded homolog 2 is a protein that in humans is encoded by the SIM2 gene.[1][2] It plays a major role in the development of the central nervous system midline as well as the construction of the face and head.[3] # Function SIM1 and SIM2 genes are Drosophila single-minded (sim) gene homologs. The Drosophila sim gene encodes a transcription factor that is a master regulator of neurogenesis of midline cells in the central nervous system. SIM2 maps within the so-called Down syndrome chromosomal region, specifically on the q arm of chromosome 21, band 22.2.[3] Based on the mapping position, its potential function as transcriptional repressor and similarity to Drosophila sim, it is proposed that SIM2 may contribute to some specific Down syndrome phenotypes[2] # Interactions SIM2 has been shown to interact with Aryl hydrocarbon receptor nuclear translocator.[4][5][6][7] When the SIM2 gene is tranfected into PC12 cells, it effects the normal cycle of cell maturation. SIM2 inhibits the expression of cyclin E, which in turn inhibits the cell's ability to pass through the G1/S checkpoint and suppresses the cell's proliferation ability. it also up-regulates the presence of p27, a growth inhibitor protein. The presence of p27 inhibits the activation of cell cycle regulatory kinases.[8] # Disease state There are three states of the gene: +/+, +/-, and -/-. When the gene is expressed as SIM2 -/-, it is considered disrupted and many physical malformations are seen, particularly in the craniofacial area. Individuals with SIM2 -/- have either a full or partial secondary palate cleft and malformations in the tongue and pterygoid processes of the sphenoid bone. These malformations cause aerophagia, or the swallowing of air, and postnatal death. Severe aerophagia leads to accumulation of air in the gastrointestinal tract, causing the belly to be distended.[3] It is thought that the over-expression of the SIM2 gene brings about some of the phenotypic deformities that are characteristic of Down syndrome. The presence of SIM2 mRNA in many parts of the brain known to show deformities in individuals with Down syndrome, as well as in the palate, oral and tongue epithelia, mandibular and hyoid bones.[3] # SIM2 Short (SIM2s) There are two known isoforms of SIM2 which play different roles in various tissues. The isoform SIM2 Short (SIM2s) has been shown to be specifically expressed in mammary gland tissue.[9] SIM2s is a splice variant which lacks exon 11 of SIM2.[10] It has been researched that SIM2s acts in mammary gland development and has tumor suppressive characteristics specifically in breast cancer.[9][11][12] In a mouse specimen, when SIM2s was not expressed in mammary epithelial cells there were development defects leading to cancer-like characteristics in the cells.[12] The defects were increased cell proliferation, cellular invasion of local stroma, loss of cellular polarity, and loss of E-cadherin cellular adhesion molecules.[12] These observations suggest that SIM2s is essential for proper mammary gland development.[12] Experiments reintroducing SIM2s in human breast cancer cells allowed for the tumor suppressive characteristics to be observed. Comparing normal human breast cells to human breast cancer cells with immunohistochemical staining showed that SIM2s was expressed more in the normal than the cancerous.[9] Reintroducing SIM2s expression in breast cancer cells showed a decrease in growth, proliferation, and invasiveness.[9] SIM2s represses the actions of the matrix metalloprotease-3 gene (MMP3) which include cell migration, cancer progression, and epithelial to mesenchymal transitions (EMT).[9] SIM2s also represses the SLUG transcription factor which in turn suppresses EMT.[12] EMT suppression allows for E-cadherin to remain and for the cell to not undergo pathological EMT associated with tumor formation.[12] These actions show the tumor suppressive effects of SIM2s in mammary epithelium. # Knockout model Scientists can purposefully "knockout" or cause the gene to be disrupted. To do this, they perform homologous recombination and eliminate the predicted start codon and the following 47 amino acids. Then the EcoRI restriction site is introduced into the chromosome.[3]

https://www.wikidoc.org/index.php/SIM2

bbcef20a6347d4a1798d3ce5b989dd0c79f8877a

wikidoc

SIX1

SIX1 Homeobox protein SIX1 (Sineoculis homeobox homolog 1) is a protein that in humans is encoded by the SIX1 gene. # Function The vertebrate SIX genes are homologs of the Drosophila 'sine oculis' (so) gene, which is expressed primarily in the developing visual system of the fly. Members of the SIX gene family encode proteins that are characterized by a divergent DNA-binding homeodomain and an upstream SIX domain, which may be involved both in determining DNA-binding specificity and in mediating protein–protein interactions. Genes in the SIX family have been shown to play roles in vertebrate and insect development or have been implicated in maintenance of the differentiated state of tissues. # Interactions SIX1 has been shown to interact with EYA1, DACH, GRO and MDFI.

SIX1 Homeobox protein SIX1 (Sineoculis homeobox homolog 1) is a protein that in humans is encoded by the SIX1 gene.[1][2][3] # Function The vertebrate SIX genes are homologs of the Drosophila 'sine oculis' (so) gene, which is expressed primarily in the developing visual system of the fly. Members of the SIX gene family encode proteins that are characterized by a divergent DNA-binding homeodomain and an upstream SIX domain, which may be involved both in determining DNA-binding specificity and in mediating protein–protein interactions. Genes in the SIX family have been shown to play roles in vertebrate and insect development or have been implicated in maintenance of the differentiated state of tissues.[supplied by OMIM][3] # Interactions SIX1 has been shown to interact with EYA1,[4] DACH, GRO and MDFI.[5]

https://www.wikidoc.org/index.php/SIX1

37f0bafcddc30bf386546a96b7f644fa3351020b

wikidoc

SIX3

SIX3 Homeobox protein SIX3 is a protein that in humans is encoded by the SIX3 gene. # Function The SIX homeobox 3 (SIX3) gene is crucial in embryonic development by providing necessary instructions for the formation of the forebrain and eye development. SIX3 is a transcription factor that binds to specific DNA sequences, controlling whether the gene is active or inactive. Activity of the SIX3 gene represses Wnt1 gene activity which ensures development of the forebrain and establishes the proper anterior posterior identity in the mammalian brain. By blocking Wnt1 activity, SIX3 is able to prevent abnormal expansion of the posterior portion of the brain into the anterior brain area. During retinal development, SIX3 has been proven to hold a key responsibility in the activation of Pax6, the master regulator of eye development. Furthermore, SIX3 assumes its activity in the PLE (presumptive lens ectoderm), the region in which the lens is expected to develop. If its presence is removed from this region, the lens fails to thicken and construct itself to its proper morphological state. Also, SIX3 plays a strategic role in the activation of SOX2. SIX3 has also been proven to play a role in repression of selected members of the Wnt family. In retinal development, SIX3 is responsible for the repression of Wnt8b. Also, in forebrain development, SIX3 is responsible for the repression of Wnt1 and activation of SHH, Sonic Hedgehog gene. # Clinical significance Mutations in SIX3 are the cause of a severe brain malformation, called holoprosencephaly type 2 (HPE2). In HPE2, the brain fails to separate into two hemispheres during early embryonic development, leading to eye and brain malformations, which result in serious facial abnormalities. A mutant zebrafish knockout model has been developed, in which the anterior part of the head was missing due to the atypical increase of Wnt1 activity. When injected with SIX3, these zebrafish embryos were able to successfully develop a normal forebrain. When SIX3 was turned off in mice, resulting in a lack of retina formation due to excessive expression of Wnt8b in the region where the forebrain normally develops. Both of these studies demonstrate the importance of SIX3 activity in brain and eye development. # Interactions SIX3 has been shown to interact with TLE1 and Neuron-derived orphan receptor 1.

SIX3 Homeobox protein SIX3 is a protein that in humans is encoded by the SIX3 gene.[1][2][3] # Function The SIX homeobox 3 (SIX3) gene is crucial in embryonic development by providing necessary instructions for the formation of the forebrain and eye development. SIX3 is a transcription factor that binds to specific DNA sequences, controlling whether the gene is active or inactive. Activity of the SIX3 gene represses Wnt1 gene activity which ensures development of the forebrain and establishes the proper anterior posterior identity in the mammalian brain. By blocking Wnt1 activity, SIX3 is able to prevent abnormal expansion of the posterior portion of the brain into the anterior brain area. During retinal development, SIX3 has been proven to hold a key responsibility in the activation of Pax6, the master regulator of eye development. Furthermore, SIX3 assumes its activity in the PLE (presumptive lens ectoderm), the region in which the lens is expected to develop. If its presence is removed from this region, the lens fails to thicken and construct itself to its proper morphological state. Also, SIX3 plays a strategic role in the activation of SOX2. SIX3 has also been proven to play a role in repression of selected members of the Wnt family. In retinal development, SIX3 is responsible for the repression of Wnt8b. Also, in forebrain development, SIX3 is responsible for the repression of Wnt1 and activation of SHH, Sonic Hedgehog gene. # Clinical significance Mutations in SIX3 are the cause of a severe brain malformation, called holoprosencephaly type 2 (HPE2). In HPE2, the brain fails to separate into two hemispheres during early embryonic development, leading to eye and brain malformations, which result in serious facial abnormalities.[2] A mutant zebrafish knockout model has been developed, in which the anterior part of the head was missing due to the atypical increase of Wnt1 activity. When injected with SIX3, these zebrafish embryos were able to successfully develop a normal forebrain.[4][5] When SIX3 was turned off in mice, resulting in a lack of retina formation due to excessive expression of Wnt8b in the region where the forebrain normally develops.[6] Both of these studies demonstrate the importance of SIX3 activity in brain and eye development. # Interactions SIX3 has been shown to interact with TLE1[7] and Neuron-derived orphan receptor 1.[8][9]

https://www.wikidoc.org/index.php/SIX3

7f6aeef0e5e010f6eb1b5019ea03cb8f753538b0

wikidoc

SKA2

SKA2 Spindle and kinetochore-associated protein 2 is a protein that in humans is encoded by the SKA2 gene found in chromosome 17. SKA2 is a part of a spindle and kinetochore associated complex also including SKA1 and SKA3 which is responsible for onset of the anaphase in mitosis by regulating chromosomal segregation. SKA2 may function as a prognostic gene marker for identifying lung cancer as well as a proposed biomarker for suicidal tendencies and post-traumatic stress disorders. The SKA2 gene contains one single-nucleotide polymorphism (SNP) rs7208505 located in the 3' UTR. This genetic variant containing a cytosine (existing in the less common allele) instead of thymine along with epigenetic modification (such as DNA methylation) is correlated with suicidal tendencies and post-traumatic stress. # Discovery SKA2 protein was first documented as a product of as hypothetical gene FAM33A part of a Spindle and Kinetochore (KT)- associated complex necessary for timely anaphase onset. SKA2 was identified as the partner of SKA1, hence the name in 2006. Later on the 3rd component of the SKA complex was mass spectrometrically identified as C13Orf3 later referred to as SKA3. This complex plays an important role in the cell during mitotic transition from the metaphase to the anaphase. # Protein structure and sub-cellular localization SKA2 gene product is a 121 amino acid long chain and a molecular weight of 14,188 Da containing mainly 3 helices. Homologues of SKA2 protein being very small are found in several vertebrates but absent in invertebrates. This protein mainly localizes in the condensed chromosome and to the outer spindle and kinetochore microtubules during mitosis. The SKA2 proteins localizes to the mitotic spindle and kinetochore associated proteins such as SKA1 and SKA3. # Function The SKA2 is a part of the larger spindle and kinetochore complex which is a sub-complex of the outer kinetochore and binds to the microtubules. This complex is essential for the correctly timed onset of anaphase during mitosis by helping in the chromosomal segregation and aids in the movement of microspheres along a microtubule in a depolymerisation-coupled manner, since it is a direct component in the kinetochore-microtubule interface along with directly associating with the microtubules as assemblies. A reduced expression of SKA2 results in the loss of the complex from the kinetochore, however this loss of SKA-complex doesn’t affect the overall structure of the Kinetochore yet the fibres show increased cold-sensitivity due to the loss. The cell goes through a prolonged delay in a metaphase-like state. It has been concluded that SKA2 regulates the maintenance of the metaphase plate and silencing of the spindle checkpoint leading to the onset of anaphase during mitosis. SKA2 also interacts with the glucocorticoid receptor aiding in the chaperoning of the receptor in the nucleus. # Clinical significance ## Suicidal tendencies and post-traumatic stress disorder The DNA methylation of SKA2 gene and the Single-nucleotide polymorphism rs7208505 genotype may have effects on suicidal behaviour according to linear model suggested by a study in 2014. The genotype rs7208505 contains a single nucleotide polymorphism (SNP) containing a Cytosine variant allele instead of Thymine present in the common allele. This SNP allows the dinucleotide repeat (CpG) elements to occur providing a gene segment for methylation. Thus DNA methylation alone may be the primary factor conferring risk of suicidal behaviour. A study of allele of rs7208505 in different ethnic groups along with numerous psychiatric diagnosis suggested that the variation in SKA2 may mediate risk for suicidal behaviours that progress to attempt to suicide. ## Lung cancer The SKA2 gene along with PRR11 gene as a pair is essential for the development of lung cancer. The pair of genes are separated by a 548 bp intergenic region, and having a classical head-to-head gene pair motif share a prototypical bidirectional promoter containing a common CCAAT element. This promoter is regulated by NF-Y is a sequence specific transcription factor and has long been considered an activator of genes since it contains particular properties suitable to regulate bidirectional promotor with the CCAAT box sequence. This bidirectional promotors couple expression of 2 genes (protein coding) involved in the same biochemical process to allow a synchronized temporal or environmental control. The 2 genes SKA2 and PRR11 are vital for accelerated growth and motility of lung cancer cells and have prognostic value for patients. Along with SKA2, PRR11 also plays a major role in regulating cell cycle progression but from the late S phase to mitosis. Thus, having vital roles to play in cell cycle progression at different stages, SKA2 and PRR11 may co-ordinately regulate lung cancer proliferation by deregulation of cell cycle progression. Since the transcription of SKA2 gene produces the protein coding mRNA SKA2 along with 2 other introns miRNA301a and miRNAA454, hence the function of the gene is not limited to production of a protein. These introns participate in tumorigenesis since miRNA301a regulates PTEN, NKRF, SMAD4 and PIAS3 and miRNAA454 targets SMAD4 playing an oncogenic role in human colon cancer. # Interactions - SKA1 - SKA3 - GR (Glucocorticoid receptor)

SKA2 Spindle and kinetochore-associated protein 2 is a protein that in humans is encoded by the SKA2 gene found in chromosome 17. SKA2 is a part of a spindle and kinetochore associated complex also including SKA1 and SKA3 which is responsible for onset of the anaphase in mitosis by regulating chromosomal segregation.[1][2] SKA2 may function as a prognostic gene marker for identifying lung cancer[3] as well as a proposed biomarker for suicidal tendencies and post-traumatic stress disorders.[4][5] The SKA2 gene contains one single-nucleotide polymorphism (SNP) rs7208505 located in the 3' UTR. This genetic variant containing a cytosine (existing in the less common allele) instead of thymine along with epigenetic modification (such as DNA methylation) is correlated with suicidal tendencies and post-traumatic stress.[4] # Discovery SKA2 protein was first documented as a product of as hypothetical gene FAM33A part of a Spindle and Kinetochore (KT)- associated complex necessary for timely anaphase onset. SKA2 was identified as the partner of SKA1, hence the name in 2006.[2] Later on the 3rd component of the SKA complex was mass spectrometrically identified as C13Orf3 later referred to as SKA3.[6] This complex plays an important role in the cell during mitotic transition from the metaphase to the anaphase.[2] # Protein structure and sub-cellular localization SKA2 gene product is a 121 amino acid long chain and a molecular weight of 14,188 Da containing mainly 3 helices.[7] Homologues of SKA2 protein being very small are found in several vertebrates but absent in invertebrates.[2] This protein mainly localizes in the condensed chromosome and to the outer spindle and kinetochore microtubules during mitosis.[2] The SKA2 proteins localizes to the mitotic spindle and kinetochore associated proteins such as SKA1 and SKA3.[8] # Function The SKA2 is a part of the larger spindle and kinetochore complex which is a sub-complex of the outer kinetochore and binds to the microtubules.[2][8][9] This complex is essential for the correctly timed onset of anaphase during mitosis by helping in the chromosomal segregation[2] and aids in the movement of microspheres along a microtubule in a depolymerisation-coupled manner, since it is a direct component in the kinetochore-microtubule interface along with directly associating with the microtubules as assemblies.[9] A reduced expression of SKA2 results in the loss of the complex from the kinetochore, however this loss of SKA-complex doesn’t affect the overall structure of the Kinetochore yet the fibres show increased cold-sensitivity due to the loss. The cell goes through a prolonged delay in a metaphase-like state.[2] It has been concluded that SKA2 regulates the maintenance of the metaphase plate and silencing of the spindle checkpoint leading to the onset of anaphase during mitosis.[2] SKA2 also interacts with the glucocorticoid receptor aiding in the chaperoning of the receptor in the nucleus.[10] # Clinical significance ## Suicidal tendencies and post-traumatic stress disorder The DNA methylation of SKA2 gene and the Single-nucleotide polymorphism rs7208505 genotype may have effects on suicidal behaviour according to linear model suggested by a study in 2014. The genotype rs7208505 contains a single nucleotide polymorphism (SNP) containing a Cytosine variant allele instead of Thymine present in the common allele. This SNP allows the dinucleotide repeat (CpG) elements to occur providing a gene segment for methylation. Thus DNA methylation alone may be the primary factor conferring risk of suicidal behaviour. A study of allele of rs7208505 in different ethnic groups along with numerous psychiatric diagnosis suggested that the variation in SKA2 may mediate risk for suicidal behaviours that progress to attempt to suicide.[4] ## Lung cancer The SKA2 gene along with PRR11 gene as a pair is essential for the development of lung cancer. The pair of genes are separated by a 548 bp intergenic region, and having a classical head-to-head gene pair motif share a prototypical bidirectional promoter containing a common CCAAT element.[11][12] This promoter is regulated by NF-Y is a sequence specific transcription factor and has long been considered an activator of genes since it contains particular properties suitable to regulate bidirectional promotor with the CCAAT box sequence. This bidirectional promotors couple expression of 2 genes (protein coding) involved in the same biochemical process to allow a synchronized temporal or environmental control. The 2 genes SKA2 and PRR11 are vital for accelerated growth and motility of lung cancer cells and have prognostic value for patients. Along with SKA2, PRR11 also plays a major role in regulating cell cycle progression but from the late S phase to mitosis.[2][13] Thus, having vital roles to play in cell cycle progression at different stages, SKA2 and PRR11 may co-ordinately regulate lung cancer proliferation by deregulation of cell cycle progression.[3] Since the transcription of SKA2 gene produces the protein coding mRNA SKA2 along with 2 other introns miRNA301a and miRNAA454, hence the function of the gene is not limited to production of a protein.[3] These introns participate in tumorigenesis since miRNA301a regulates PTEN, NKRF, SMAD4 and PIAS3 and miRNAA454 targets SMAD4 playing an oncogenic role in human colon cancer.[14] # Interactions - SKA1 - SKA3 - GR (Glucocorticoid receptor)

https://www.wikidoc.org/index.php/SKA2

0d40080a173418084e2e0f841309f87af9cdfef8

wikidoc

SKP2

SKP2 S-phase kinase-associated protein 2 is an enzyme that in humans is encoded by the SKP2 gene. # Structure and function Skp2 contains 424 residues in total with the ~40 amino acid F-box domain lying closer to the N-terminal region at the 94-140 position and the C-terminal region forming a concave surface consisting of ten leucine-rich repeats (LRRs). The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which often—but not always—recognize substrates in a phosphorylation-dependent manner. In this SCF complex, Skp2 acts as the substrate recognition factor. ## F-box Domain The F-box proteins are divided into three classes: Fbxws containing WD40 repeat domains, Fbxls containing leucine-rich repeats, and Fbxos containing either different protein–protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbxls class. In addition to an F-box, this protein contains 10 tandem leucine-rich repeats. Alternative splicing of this gene generates 2 transcript variants encoding different isoforms. After the tenth LRR, the ~30-residue C-terminal tail turns back towards the first LRR, forming what has been referred to as a ‘safety-belt’ that might aid to pin down substrates into the concave surface formed by the LRRs. Skp2 forms a stable complex with the cyclin A-CDK2 S-phase kinase. It specifically recognizes and promotes the degradation of phosphorylated cyclin-dependent kinase inhibitor 1B (CDKN1B, also referred to as p27 or KIP1) predominantly in S, G2 phase, and the initial part of the M phase. The degradation of p27 via Skp2 requires the accessory protein CKS1B. To prevent premature degradation of p27, Skp2 levels are kept low during early and mid-G1 due to the APC/CCdh1ubiquitin ligase, which mediates the ubiquitylation of Skp2. Phosphorylation of Ser64 and, to a lesser extent, Ser72 of Skp2 contributes to the stabilization of Skp2 by preventing its association with APC/CCdh1; however, Skp2 phosphorylation on these residues is dispensable for its subcellular localization and for Skp2 assembly into an active SCF ubiquitin ligase. ## Role in cell cycle regulation Progression through the cell cycle is tightly regulated by cyclin-dependent kinases (CDKs), and their interactions with cyclins and CDK inhibitors (CKIs). Relative amounts of these signals oscillate during each stage of the cell cycle due to periodic proteolysis; the ubiquitin-proteasome system mediates the degradation of these mitotic regulatory proteins, controlling their intracellular concentrations. These and other proteins are recognized and degraded by the proteasome from the sequential action of three enzymes: E1 (ubiquitin-activating enzyme), one of many E2s (ubiquitin-conjugating enzyme), and one of many E3 ubiquitin ligase. The specificity of ubiquitination is provided by the E3 ligases; these ligases physically interact with the target substrates. Skp2 is the substrate recruiting component of the SCFSkp2 complex, which targets cell cycle control elements, such as p27 and p21. Here, SKP2 has been implicated in double negative feedback loops with both p21 and p27, that control cell cycle entry and G1/S transition. # Clinical significance Skp2 behaves as an oncogene in cell systems and is an established protooncogene causally involved in the pathogenesis of lymphomas. One of the most critical CDK inhibitors involved in cancer pathogenesis is p27Kip1, which is involved primarily in inhibiting cyclin E-CDK2 complexes (and to a lesser extent cyclin D-CDK4 complexes). Levels of p27Kip1 (like all other CKIs) rise and fall in cells as they either exit or re-enter the cell cycle, these levels are not modulated at the transcriptional level, but by the actions of the SCFSkp2 complex in recognizing p27Kip1 and tagging it for destruction in the proteasome system. It has been shown that as cells enter G0 phase, reducing levels of Skp2 explain the increase in p27Kip1, creating an apparent inverse relationship between Skp2 and p27Kip1. Robust evidence has been amassed that strongly suggests Skp2 plays an important role in cancer. ## Overexpression Overexpression of Skp2 is frequently observed in human cancer progression and metastasis, and evidence suggests that Skp2 plays a proto-oncogenic role both in vitro and in vivo. Skp2 overexpression has been seen in: lymphomas, prostate cancer, melanoma, nasopharyngeal carcinoma, pancreatic cancer, and breast carcinomas. Additionally, overexpression of Skp2 is correlated with a poor prognosis in breast cancer. As one would expect, Skp2 overexpression promotes growth and tumorigenesis in a xenograft tumor model. By extension of this fact, Skp2 inactivation profoundly restricts cancer development by triggering a massive cellular senescence and/or apoptosis response that is surprisingly observed only in oncogenic conditions in vivo. This response is triggered in a p19Arf/p53-independent, but p27-dependent manner. Using a Skp2 knockout mouse model, multiple groups have shown Skp2 is required for cancer development in different conditions of tumor promotion, including PTEN, ARF, pRB in activation as well as Her2/Neu overexpression. Genetic approaches have demonstrated that Skp2 deficiency inhibits cancer development in multiple mouse models by inducing p53-independent cellular senescence and blocking Akt-mediated aerobic glycolysis. Akt activation by Skp2 is linked to aerobic glycolysis, as Skp2 deficiency impairs Akt activation, Glut1 expression, and glucose uptake thereby promoting cancer development. ## Potential use as a clinical target Skp2 is of considerable interest as a novel and attractive target for cancer therapeutical development, as disrupting the SCF complex will result in increased levels of p27, which will inhibit aberrant cellular proliferation. Although Skp2 is an enzyme, its function requires the assembly of the other members of the SCF complex. As Skp2 is the rate-limiting component of the SCF complex, effective inhibitors should be focused on the interfaces of Skp2 with the other members of the SCF complex, which is much more difficult than traditional enzyme inhibition. Small molecule inhibitors of the binding site between Skp2 and the accessory protein Cks1 have been discovered, and these inhibitors induce p27 accumulation in a Skp2-dependent manner and promote cell cycle arrest. Another recent discovery were inhibitors of the Skp1/Skp2 interface that resulted in: restoring p27 levels, suppressing survival, trigger p53-independent senescence, exhibit potent antitumor activity in multiple animal models, and were also found to affect Akt-mediated glycolysis. Skp2 is a potential target for pten-deficient cancers. # Interactions SKP2 has been shown to interact with: - CCNA2, - CDK2, - CDKN1A - CDKN1B - CKS1B, - CDT1, - CUL1 - E2F1, - ORC1L, and - SKP1A.

SKP2 S-phase kinase-associated protein 2 is an enzyme that in humans is encoded by the SKP2 gene.[1][2] # Structure and function Skp2 contains 424 residues in total with the ~40 amino acid F-box domain lying closer to the N-terminal region at the 94-140 position and the C-terminal region forming a concave surface consisting of ten leucine-rich repeats (LRRs).[3] The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which often—but not always—recognize substrates in a phosphorylation-dependent manner. In this SCF complex, Skp2 acts as the substrate recognition factor.[4][5][6] ## F-box Domain The F-box proteins are divided into three classes: Fbxws containing WD40 repeat domains, Fbxls containing leucine-rich repeats, and Fbxos containing either different protein–protein interaction modules or no recognizable motifs.[7] The protein encoded by this gene belongs to the Fbxls class. In addition to an F-box, this protein contains 10 tandem leucine-rich repeats. Alternative splicing of this gene generates 2 transcript variants encoding different isoforms. After the tenth LRR, the ~30-residue C-terminal tail turns back towards the first LRR, forming what has been referred to as a ‘safety-belt’ that might aid to pin down substrates into the concave surface formed by the LRRs.[8] Skp2 forms a stable complex with the cyclin A-CDK2 S-phase kinase. It specifically recognizes and promotes the degradation of phosphorylated cyclin-dependent kinase inhibitor 1B (CDKN1B, also referred to as p27 or KIP1) predominantly in S, G2 phase, and the initial part of the M phase.[9][10] The degradation of p27 via Skp2 requires the accessory protein CKS1B.[11][12] To prevent premature degradation of p27, Skp2 levels are kept low during early and mid-G1 due to the APC/CCdh1ubiquitin ligase, which mediates the ubiquitylation of Skp2.[13][14] Phosphorylation of Ser64 and, to a lesser extent, Ser72 of Skp2 contributes to the stabilization of Skp2 by preventing its association with APC/CCdh1; however, Skp2 phosphorylation on these residues is dispensable for its subcellular localization and for Skp2 assembly into an active SCF ubiquitin ligase.[15][16][17][18][19] ## Role in cell cycle regulation Progression through the cell cycle is tightly regulated by cyclin-dependent kinases (CDKs), and their interactions with cyclins and CDK inhibitors (CKIs). Relative amounts of these signals oscillate during each stage of the cell cycle due to periodic proteolysis;[20] the ubiquitin-proteasome system mediates the degradation of these mitotic regulatory proteins, controlling their intracellular concentrations.[21][22] These and other proteins are recognized and degraded by the proteasome from the sequential action of three enzymes: E1 (ubiquitin-activating enzyme), one of many E2s (ubiquitin-conjugating enzyme), and one of many E3 ubiquitin ligase.[23] The specificity of ubiquitination is provided by the E3 ligases; these ligases physically interact with the target substrates. Skp2 is the substrate recruiting component of the SCFSkp2 complex, which targets cell cycle control elements, such as p27 and p21.[24][25][26] Here, SKP2 has been implicated in double negative feedback loops with both p21 and p27, that control cell cycle entry and G1/S transition.[27][28] # Clinical significance Skp2 behaves as an oncogene in cell systems[29] and is an established protooncogene causally involved in the pathogenesis of lymphomas.[30] One of the most critical CDK inhibitors involved in cancer pathogenesis is p27Kip1, which is involved primarily in inhibiting cyclin E-CDK2 complexes (and to a lesser extent cyclin D-CDK4 complexes).[31] Levels of p27Kip1 (like all other CKIs) rise and fall in cells as they either exit or re-enter the cell cycle, these levels are not modulated at the transcriptional level, but by the actions of the SCFSkp2 complex in recognizing p27Kip1 and tagging it for destruction in the proteasome system.[20] It has been shown that as cells enter G0 phase, reducing levels of Skp2 explain the increase in p27Kip1, creating an apparent inverse relationship between Skp2 and p27Kip1.[13] Robust evidence has been amassed that strongly suggests Skp2 plays an important role in cancer. ## Overexpression Overexpression of Skp2 is frequently observed in human cancer progression and metastasis, and evidence suggests that Skp2 plays a proto-oncogenic role both in vitro and in vivo.[4] Skp2 overexpression has been seen in: lymphomas,[32] prostate cancer,[33] melanoma,[34] nasopharyngeal carcinoma,[35][36] pancreatic cancer,[37] and breast carcinomas.[38][39] Additionally, overexpression of Skp2 is correlated with a poor prognosis in breast cancer.[40][41] As one would expect, Skp2 overexpression promotes growth and tumorigenesis in a xenograft tumor model.[42] By extension of this fact, Skp2 inactivation profoundly restricts cancer development by triggering a massive cellular senescence and/or apoptosis response that is surprisingly observed only in oncogenic conditions in vivo.[43] This response is triggered in a p19Arf/p53-independent, but p27-dependent manner.[43] Using a Skp2 knockout mouse model, multiple groups have shown Skp2 is required for cancer development in different conditions of tumor promotion, including PTEN, ARF, pRB in activation as well as Her2/Neu overexpression.[44] Genetic approaches have demonstrated that Skp2 deficiency inhibits cancer development in multiple mouse models by inducing p53-independent cellular senescence and blocking Akt-mediated aerobic glycolysis. Akt activation by Skp2 is linked to aerobic glycolysis, as Skp2 deficiency impairs Akt activation, Glut1 expression, and glucose uptake thereby promoting cancer development.[45] ## Potential use as a clinical target Skp2 is of considerable interest as a novel and attractive target for cancer therapeutical development, as disrupting the SCF complex will result in increased levels of p27, which will inhibit aberrant cellular proliferation. Although Skp2 is an enzyme, its function requires the assembly of the other members of the SCF complex. As Skp2 is the rate-limiting component of the SCF complex, effective inhibitors should be focused on the interfaces of Skp2 with the other members of the SCF complex, which is much more difficult than traditional enzyme inhibition. Small molecule inhibitors of the binding site between Skp2 and the accessory protein Cks1 have been discovered, and these inhibitors induce p27 accumulation in a Skp2-dependent manner and promote cell cycle arrest.[46] Another recent discovery were inhibitors of the Skp1/Skp2 interface that resulted in: restoring p27 levels, suppressing survival, trigger p53-independent senescence, exhibit potent antitumor activity in multiple animal models, and were also found to affect Akt-mediated glycolysis.[47] Skp2 is a potential target for pten-deficient cancers.[43] # Interactions SKP2 has been shown to interact with: - CCNA2,[48][49] - CDK2,[48][49][50] - CDKN1A[51] - CDKN1B[11][52][53] - CKS1B,[11][12][52][54][55] - CDT1,[56] - CUL1[5][49][56][57][58][59] - E2F1,[49] - ORC1L,[60] and - SKP1A.[57][61][62][63][64]

https://www.wikidoc.org/index.php/SKP2

ca90ee2707d7e6cbbcf6cb219b41e2a1a530e9f3

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SLBP

SLBP Histone RNA hairpin-binding protein or stem-loop binding protein (SLBP) is a protein that in humans is encoded by the SLBP gene. # Species distribution SLBP has been cloned from humans, C. elegans, D. melanogaster, X. laevis, and sea urchins. The full length human protein has 270 amino acids (31 kDa) with a centrally located RNA binding domain (RBD). The 75 amino acid RBD is well conserved across species, however the remainder of SLBP is highly divergent in most organisms and not homologous to any other protein in the eukaryotic genomes. # Function This gene encodes a protein that binds to the histone 3' UTR stem-loop structure in replication-dependent histone mRNAs. Histone mRNAs do not contain introns or polyadenylation signals, and are processed by a single endonucleolytic cleavage event downstream of the stem-loop. The stem-loop structure is essential for efficient processing of the histone pre-mRNA but this structure also controls the transport, translation and stability of histone mRNAs. SLBP expression is regulated during S-phase of the cell cycle, increasing more than 10-fold during the latter part of G1. All SLBP proteins are capable of forming a highly stable complex with histone stem-loop RNA. Complex formation with the histone mRNA stem-loop is achieved by a novel three-helix bundle fold. SLBP proteins also recognize the tetraloop structure of the histone hairpin, the base of the stem, and the 5' flanking region. The crystal structure of human SLBP in complex with the stem-loop RNA as well as the exonuclease Eri1 reveals that the Arg181 residue of SLBP specifically interacts with the second guanine base in the RNA stem. The rest of the protein is intrinsically disordered in fruit-flies as well as in humans. A unique feature of the SLBP RBD is that it is phosphorylated in its RNA binding domain at the Thr171 residue. The SLBP RBD also undergoes proline isomerization about this sequence and is a substrate for the prolyl isomerase Pin1. The N-terminal domain of human SLBP is required for translation activation of histone mRNAs via its interaction with SLIP1. SLBP also interacts with the CBP80 associated protein CTIF to facilitate rapid degradation of histone mRNAs. SLBP is a phosphoprotein and besides T171, it is also phosphorylated at Ser7, Ser20, Ser23, Thr60, Thr61 in mammalian cells. The phosphorylation at Thr60 is mediated by CK2 and Thr61 is by Cyclin A/Cdk1.

SLBP Histone RNA hairpin-binding protein or stem-loop binding protein (SLBP) is a protein that in humans is encoded by the SLBP gene.[1][2][3] # Species distribution SLBP has been cloned from humans, C. elegans, D. melanogaster, X. laevis, and sea urchins. The full length human protein has 270 amino acids (31 kDa) with a centrally located RNA binding domain (RBD). The 75 amino acid RBD is well conserved across species, however the remainder of SLBP is highly divergent in most organisms and not homologous to any other protein in the eukaryotic genomes. # Function This gene encodes a protein that binds to the histone 3' UTR stem-loop structure in replication-dependent histone mRNAs. Histone mRNAs do not contain introns or polyadenylation signals, and are processed by a single endonucleolytic cleavage event downstream of the stem-loop. The stem-loop structure is essential for efficient processing of the histone pre-mRNA but this structure also controls the transport, translation and stability of histone mRNAs. SLBP expression is regulated during S-phase of the cell cycle, increasing more than 10-fold during the latter part of G1. All SLBP proteins are capable of forming a highly stable complex with histone stem-loop RNA. Complex formation with the histone mRNA stem-loop is achieved by a novel three-helix bundle fold. SLBP proteins also recognize the tetraloop structure of the histone hairpin, the base of the stem, and the 5' flanking region. The crystal structure of human SLBP in complex with the stem-loop RNA as well as the exonuclease Eri1 reveals that the Arg181 residue of SLBP specifically interacts with the second guanine base in the RNA stem.[4] The rest of the protein is intrinsically disordered in fruit-flies as well as in humans. A unique feature of the SLBP RBD is that it is phosphorylated in its RNA binding domain at the Thr171 residue. The SLBP RBD also undergoes proline isomerization about this sequence and is a substrate for the prolyl isomerase Pin1. The N-terminal domain of human SLBP is required for translation activation of histone mRNAs via its interaction with SLIP1. SLBP also interacts with the CBP80 associated protein CTIF to facilitate rapid degradation of histone mRNAs. SLBP is a phosphoprotein and besides T171, it is also phosphorylated at Ser7, Ser20, Ser23, Thr60, Thr61 in mammalian cells. The phosphorylation at Thr60 is mediated by CK2 and Thr61 is by Cyclin A/Cdk1.[3]

https://www.wikidoc.org/index.php/SLBP

da4207ed7a0bd9438a0e677e49791b140ae50cd6

wikidoc

SLPI

SLPI Antileukoproteinase, also known as secretory leukocyte protease inhibitor (SLPI), is an enzyme that in humans is encoded by the SLPI gene. SLPI is a highly cationic single-chain protein with eight intramolecular disulfide bonds. It is found in large quantities in bronchial, cervical, and nasal mucosa, saliva, and seminal fluids. SLPI inhibits human leukocyte elastase, human cathepsin G, human trypsin, neutrophil elastase, and mast cell chymase. X-ray crystallography has shown that SLPI has two homologous domains of 53 and 54 amino acids, one of which exhibits anti-protease activity (C-terminal domain). The other domain (N-terminal domain) is not known to have any function. # Function This gene encodes a secreted inhibitor which protects epithelial tissues from serine proteases. It is found in various secretions including seminal plasma, cervical mucus, and bronchial secretions, and has affinity for trypsin, leukocyte elastase, and cathepsin G. Its inhibitory effect contributes to the immune response by protecting epithelial surfaces from attack by endogenous proteolytic enzymes; the protein is also thought to have broad-spectrum anti-biotic activity. # Clinical significance The gene for SLPI is expressed by cells at many mucosal surfaces located in the tissues of the lungs, cervix, seminal vesicles, and parotid ducts. SLPI is also one of the dominantly present proteins in nasal epithelial lining fluid and other nasal secretions. Tissue SLPI expression reveals a clear compartmentalization, being highest in the endocervix and lowest in the endometrium of postmenopausal women. Hormonal treatment differentially modulates tissue SLPI expression along the reproductive tract . Many diseases, such as emphysema, cystic fibrosis, and idiopathic pulmonary fibrosis, are characterized by increased levels of neutrophil elastase. SLPI is one of the major defenses against the destruction of pulmonary tissues and epithelial tissues by neutrophil elastase. SLPI is considered to be the predominant elastase inhibitor in secretions, while α1-antitrypsin is the predominant elastase inhibitor in tissues. Several diseases, including those listed, are actually the result of SLPI and α1-antitrypsin defenses being overwhelmed by neutrophil elastase. It has been suggested that recombinant human SLPI be administered to treat symptoms of cystic fibrosis, genetic emphysema, and asthma. In addition, SLPI has occasionally been monitored in an effort to coordinate its levels with different pathological conditions. Increased levels of SLPI in nasal secretions and bronchoalveolar fluids may be denotive of inflammatory lung conditions or allergic reactions, and increased levels of SLPI in plasma may be indicative of pneumonia. Increased levels of SLPI in saliva and plasma may also be an indicator of HIV infection. This is evident due to the virtual nonexistence of HIV transmission through oral-to-oral contact. This antiviral activity is due to the interference of SLPI in events that are mediated by protease, such as entry into the host cell and replication of viral genetic material. Studies have shown that decreasing levels of SLPI in saliva also decreases its anti-HIV activity. What makes SLPI such a topic of interest is that it exhibits anti-HIV properties in physiological conditions, rather than artificial ones. Furthermore, it has been shown that there is an inverse correlation between the levels of SLPI and high-risk Human Papillomavirus (HPV) infection, demonstrating that high levels of SLPI confer protection against HPV infection. # Interactions SLPI has been shown to interact with PLSCR1 and PLSCR4 on the plasma membrane of T-cells, specifically in the proximity of CD4. This interaction is hypothesized to be one of the ways SLPI inhibits HIV infection. Additionally, it has been shown that SLPI is able to bind the Annexin A2/S100A10 heterotetramer (A2t), a co-factor HIV infection, on the surface of macrophages. This interaction with A2t has also been shown to block HPV uptake and infection of epithelial cells.

SLPI Antileukoproteinase, also known as secretory leukocyte protease inhibitor (SLPI), is an enzyme that in humans is encoded by the SLPI gene.[1][2][3] SLPI is a highly cationic single-chain protein with eight intramolecular disulfide bonds. It is found in large quantities in bronchial, cervical, and nasal mucosa, saliva, and seminal fluids. SLPI inhibits human leukocyte elastase, human cathepsin G, human trypsin, neutrophil elastase, and mast cell chymase. X-ray crystallography has shown that SLPI has two homologous domains of 53 and 54 amino acids, one of which exhibits anti-protease activity (C-terminal domain). The other domain (N-terminal domain) is not known to have any function. # Function This gene encodes a secreted inhibitor which protects epithelial tissues from serine proteases. It is found in various secretions including seminal plasma, cervical mucus, and bronchial secretions, and has affinity for trypsin, leukocyte elastase, and cathepsin G. Its inhibitory effect contributes to the immune response by protecting epithelial surfaces from attack by endogenous proteolytic enzymes; the protein is also thought to have broad-spectrum anti-biotic activity.[3] # Clinical significance The gene for SLPI is expressed by cells at many mucosal surfaces located in the tissues of the lungs, cervix, seminal vesicles, and parotid ducts. SLPI is also one of the dominantly present proteins in nasal epithelial lining fluid and other nasal secretions. Tissue SLPI expression reveals a clear compartmentalization, being highest in the endocervix and lowest in the endometrium of postmenopausal women. Hormonal treatment differentially modulates tissue SLPI expression along the reproductive tract [4]. Many diseases, such as emphysema, cystic fibrosis, and idiopathic pulmonary fibrosis, are characterized by increased levels of neutrophil elastase. SLPI is one of the major defenses against the destruction of pulmonary tissues and epithelial tissues by neutrophil elastase. SLPI is considered to be the predominant elastase inhibitor in secretions, while α1-antitrypsin is the predominant elastase inhibitor in tissues. Several diseases, including those listed, are actually the result of SLPI and α1-antitrypsin defenses being overwhelmed by neutrophil elastase. It has been suggested that recombinant human SLPI be administered to treat symptoms of cystic fibrosis, genetic emphysema, and asthma. In addition, SLPI has occasionally been monitored in an effort to coordinate its levels with different pathological conditions. Increased levels of SLPI in nasal secretions and bronchoalveolar fluids may be denotive of inflammatory lung conditions or allergic reactions, and increased levels of SLPI in plasma may be indicative of pneumonia.[5] Increased levels of SLPI in saliva and plasma may also be an indicator of HIV infection. This is evident due to the virtual nonexistence of HIV transmission through oral-to-oral contact. This antiviral activity is due to the interference of SLPI in events that are mediated by protease, such as entry into the host cell and replication of viral genetic material. Studies have shown that decreasing levels of SLPI in saliva also decreases its anti-HIV activity.[5][6][7][8] What makes SLPI such a topic of interest is that it exhibits anti-HIV properties in physiological conditions, rather than artificial ones.[5] Furthermore, it has been shown that there is an inverse correlation between the levels of SLPI and high-risk Human Papillomavirus (HPV) infection, demonstrating that high levels of SLPI confer protection against HPV infection.[9][10][11] # Interactions SLPI has been shown to interact with PLSCR1 and PLSCR4 on the plasma membrane of T-cells, specifically in the proximity of CD4.[12][13] This interaction is hypothesized to be one of the ways SLPI inhibits HIV infection. Additionally, it has been shown that SLPI is able to bind the Annexin A2/S100A10 heterotetramer (A2t), a co-factor HIV infection, on the surface of macrophages.[14] This interaction with A2t has also been shown to block HPV uptake and infection of epithelial cells.[15]

https://www.wikidoc.org/index.php/SLPI

332b6b7b7600437072f41296273e28e45a71362a

wikidoc

SLUD

SLUD SLUD (Salivation, Lacrimation, Urination, Defecation ) is a syndrome of pathological effects indicative of massive discharge of the parasympathetic nervous system. Unlikely to occur naturally, SLUD is usually encountered only in cases of drug overdose or exposure to nerve gases. Nerve gases irreversibly inhibit the enzyme acetylcholinesterase; this results in a chronically high level of acetylcholine at cholinergic synapses throughout the body, thus chronically stimulating acetylcholine receptors throughout the body. The symptoms of SLUD are due to chronic stimulation of muscarinic acetylcholine receptors, in organs and muscles innervated by the parasympathetic nervous system: - Salivation: stimulation of the salivary glands - Lacrimation: stimulation of the lacrimal glands - Urination: relaxation of the internal urinary sphincter, and contraction of the detrusor muscles - Defecation: relaxation of the internal anal sphincter - Emesis: stimulation of brainstem emesis center One common cause of SLUD is exposure to organophosphorus insecticides, including parathion, malathion, and diazinon. These agents phosphorylate acetylcholinesterase, thereby raising the acetylcholine levels and causing SLUD.

SLUD Template:Search infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] SLUD (Salivation, Lacrimation, Urination, Defecation [and emesis]) is a syndrome of pathological effects indicative of massive discharge of the parasympathetic nervous system. Unlikely to occur naturally, SLUD is usually encountered only in cases of drug overdose or exposure to nerve gases. Nerve gases irreversibly inhibit the enzyme acetylcholinesterase; this results in a chronically high level of acetylcholine at cholinergic synapses throughout the body, thus chronically stimulating acetylcholine receptors throughout the body. The symptoms of SLUD are due to chronic stimulation of muscarinic acetylcholine receptors, in organs and muscles innervated by the parasympathetic nervous system: - Salivation: stimulation of the salivary glands - Lacrimation: stimulation of the lacrimal glands - Urination: relaxation of the internal urinary sphincter, and contraction of the detrusor muscles - Defecation: relaxation of the internal anal sphincter - Emesis: stimulation of brainstem emesis center One common cause of SLUD is exposure to organophosphorus insecticides, including parathion, malathion, and diazinon. These agents phosphorylate acetylcholinesterase, thereby raising the acetylcholine levels and causing SLUD. Template:Skin and subcutaneous tissue symptoms and signs Template:Nervous and musculoskeletal system symptoms and signs Template:Urinary system symptoms and signs Template:Cognition, perception, emotional state and behaviour symptoms and signs Template:Speech and voice symptoms and signs Template:General symptoms and signs Template:WikiDoc Sources

https://www.wikidoc.org/index.php/SLUD

8178950a35dd9ec2c9eb3ce4c10ca8993b36839d

wikidoc

SLX4

SLX4 SLX4 (also known as BTBD12 and FANCP) is a protein involved in DNA repair, where it has important roles in the final steps of homologous recombination. Mutations in the gene are associated with the disease Fanconi anemia. The version of SLX4 present in humans and other mammals acts as a sort of scaffold upon which other proteins form several different multiprotein complexes. The SLX1-SLX4 complex acts as a Holliday junction resolvase. As such, the complex cleaves the links between two homologous chromosomes that form during homologous recombination. This allows the two linked chromosomes to resolve into two unconnected double-strand DNA molecules. SLX4 also associates with RAD1, RAD10 and SAW1 in the single-strand annealing pathway of homologous recombination. The DNA repair function of SLX4 is involved in sensitivity to proton beam radiation. # Model organisms Model organisms have been prominent in the study of SLX4 function. It was identified in 2001 during a screen for lethal mutations in yeast cells lacking a functional copy of the Sgs1 protein. Based on that, SLX4 was grouped with several other proteins produced by SLX (synthetic lethal of unknown function) genes. A conditional knockout mouse line, called Slx4tm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program, a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty four tests were carried out on mutant mice and ten significant abnormalities were observed. A viability at weaning study found less homozygous mutant animals were present than predicted by Mendelian ratio. Homozygous mutant animals of both sexes were sub-fertile and homozygous females had a reduced body weight, body length, heart weight, platelet count and lean mass. Homozygotes of both sex had abnormal eye sizes, narrow eye openings, skeletal defects (including scoliosis and fusion of vertebrae), and displayed an increase in DNA instability as shown by a micronucleus test. This and further analysis revealed the mouse phenotype to model the human genetic illness, Fanconi anemia. The association was confirmed when patients with the disease were found to have mutations in their SLX4 gene.

SLX4 SLX4 (also known as BTBD12 and FANCP) is a protein involved in DNA repair, where it has important roles in the final steps of homologous recombination.[1] Mutations in the gene are associated with the disease Fanconi anemia.[2][3] The version of SLX4 present in humans and other mammals acts as a sort of scaffold upon which other proteins form several different multiprotein complexes. The SLX1-SLX4 complex acts as a Holliday junction resolvase. As such, the complex cleaves the links between two homologous chromosomes that form during homologous recombination. This allows the two linked chromosomes to resolve into two unconnected double-strand DNA molecules.[4] SLX4 also associates with RAD1, RAD10 and SAW1 in the single-strand annealing pathway of homologous recombination.[5] The DNA repair function of SLX4 is involved in sensitivity to proton beam radiation.[6] # Model organisms Model organisms have been prominent in the study of SLX4 function. It was identified in 2001 during a screen for lethal mutations in yeast cells lacking a functional copy of the Sgs1 protein. Based on that, SLX4 was grouped with several other proteins produced by SLX (synthetic lethal of unknown function) genes.[7] A conditional knockout mouse line, called Slx4tm1a(EUCOMM)Wtsi[19] was generated as part of the International Knockout Mouse Consortium program, a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[20][21][22] Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[3][17] Twenty four tests were carried out on mutant mice and ten significant abnormalities were observed.[17] A viability at weaning study found less homozygous mutant animals were present than predicted by Mendelian ratio. Homozygous mutant animals of both sexes were sub-fertile and homozygous females had a reduced body weight, body length, heart weight, platelet count and lean mass.[23] Homozygotes of both sex had abnormal eye sizes, narrow eye openings, skeletal defects (including scoliosis and fusion of vertebrae), and displayed an increase in DNA instability as shown by a micronucleus test.[17] This and further analysis revealed the mouse phenotype to model the human genetic illness, Fanconi anemia.[3][23] The association was confirmed when patients with the disease were found to have mutations in their SLX4 gene.[2]

https://www.wikidoc.org/index.php/SLX4

079d7fa061bf7ef265a6ca489e33f8aad17ad57b

wikidoc

SMC3

SMC3 Structural maintenance of chromosomes protein 3 (SMC-3) is a nuclear protein that in humans is encoded by the SMC3 gene. A post-translated modified form that is excreted is known as basement membrane-associated chondroitin proteoglycan (bamacan). # Function This gene belongs to the SMC3 subfamily of SMC proteins. The encoded protein occurs in certain cell types as either an intracellular, nuclear protein or a secreted protein. The nuclear form, known as structural maintenance of chromosomes 3, is a component of the multimeric cohesin complex that holds together sister chromatids during mitosis, enabling proper chromosome segregation. Post-translational modification of the encoded protein by the addition of chondroitin sulfate chains gives rise to the secreted proteoglycan bamacan, an abundant basement membrane protein. SMC3 protein appears to participate with other cohesins REC8, STAG3 and SMC1ß in sister-chromatid cohesion throughout the whole meiotic process in human oocytes. # Model organisms Model organisms have been used in the study of SMC3 function. A conditional knockout mouse line, called Smc3tm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty two tests were carried out on mutant mice and six significant abnormalities were observed. No homozygous mutant embryos were identified during gestation, and thus none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice. Females had a higher than normal incidence of pre-wean death in their offspring, and also had a decreased body weight. Males heterozygotes displayed a shortened, upturned snout. # Cornelia de Lange syndrome Cornelia de Lange syndrome (CdLS) is a rare genetic disorder that presents with variable clinical abnormalities including dysmorphic features, severe growth retardation, global developmental delay, and intellectual disability. SMC3 is one of five genes that have been implicated in CdLS. In one case report, a novel SMC3 gene duplication was detected in a child with failure to thrive, hypotonia and facial dysmorphic features of CdLS. The same duplication was also observed in the mother, who had milder dysmorphic facies. # Interactions SMC3 (gene) has been shown to interact with: - KIFAP3, - MXD1, - MXI1, - REC8, and - SMC1A.

SMC3 Structural maintenance of chromosomes protein 3 (SMC-3) is a nuclear protein that in humans is encoded by the SMC3 gene.[1] A post-translated modified form that is excreted is known as basement membrane-associated chondroitin proteoglycan (bamacan). # Function This gene belongs to the SMC3 subfamily of SMC proteins. The encoded protein occurs in certain cell types as either an intracellular, nuclear protein or a secreted protein. The nuclear form, known as structural maintenance of chromosomes 3, is a component of the multimeric cohesin complex that holds together sister chromatids during mitosis, enabling proper chromosome segregation. Post-translational modification of the encoded protein by the addition of chondroitin sulfate chains gives rise to the secreted proteoglycan bamacan, an abundant basement membrane protein.[1] SMC3 protein appears to participate with other cohesins REC8, STAG3 and SMC1ß in sister-chromatid cohesion throughout the whole meiotic process in human oocytes.[2] # Model organisms Model organisms have been used in the study of SMC3 function. A conditional knockout mouse line, called Smc3tm1a(EUCOMM)Wtsi[10][11] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[12][13][14] Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[8][15] Twenty two tests were carried out on mutant mice and six significant abnormalities were observed.[8] No homozygous mutant embryos were identified during gestation, and thus none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice. Females had a higher than normal incidence of pre-wean death in their offspring, and also had a decreased body weight. Males heterozygotes displayed a shortened, upturned snout.[8][15] # Cornelia de Lange syndrome Cornelia de Lange syndrome (CdLS) is a rare genetic disorder that presents with variable clinical abnormalities including dysmorphic features, severe growth retardation, global developmental delay, and intellectual disability. SMC3 is one of five genes that have been implicated in CdLS.[16] In one case report, a novel SMC3 gene duplication was detected in a child with failure to thrive, hypotonia and facial dysmorphic features of CdLS.[16] The same duplication was also observed in the mother, who had milder dysmorphic facies. # Interactions SMC3 (gene) has been shown to interact with: - KIFAP3,[17] - MXD1,[18] - MXI1,[18] - REC8,[19] and - SMC1A.[19][20][21][22]

https://www.wikidoc.org/index.php/SMC3

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SMC5

SMC5 Structural maintenance of chromosomes protein 5 is a protein encoded by the SMC5 gene in human. It is involved in the Alternative lengthening of telomeres cancer mechanism. # Role in recombination and meiosis Smc5 and Smc6 proteins form a heterodimeric ring-like structure and together with other non-SMC elements form the SMC-5/6 complex. In the worm Caenorhabditis elegans this complex interacts with the HIM-6(BLM) helicase to promote meiotic recombination intermediate processing and chromosome maturation. The SMC-5/6 complex in mouse oocytes is essential for the formation of segregation competent bivalents during meiosis. In humans, a chromosome breakage syndrome characterized by severe lung disease in early childhood is associated with a mutation in a component of the SMC-5/6 complex. Patient’s cells display chromosome rearrangements, micronuclei, sensitivity to DNA damage and defective homologous recombination.

SMC5 Structural maintenance of chromosomes protein 5 is a protein encoded by the SMC5 gene in human.[1][2] It is involved in the Alternative lengthening of telomeres cancer mechanism.[3] # Role in recombination and meiosis Smc5 and Smc6 proteins form a heterodimeric ring-like structure and together with other non-SMC elements form the SMC-5/6 complex. In the worm Caenorhabditis elegans this complex interacts with the HIM-6(BLM) helicase to promote meiotic recombination intermediate processing and chromosome maturation.[4] The SMC-5/6 complex in mouse oocytes is essential for the formation of segregation competent bivalents during meiosis.[5] In humans, a chromosome breakage syndrome characterized by severe lung disease in early childhood is associated with a mutation in a component of the SMC-5/6 complex.[6] Patient’s cells display chromosome rearrangements, micronuclei, sensitivity to DNA damage and defective homologous recombination.

https://www.wikidoc.org/index.php/SMC5

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SMC6

SMC6 Structural maintenance of chromosomes protein 6 is a protein that in humans is encoded by the SMC6 gene. It is involved in the Alternative lengthening of telomeres cancer mechanism. # Role in recombination and meiosis Smc6 and Smc5 proteins form a heterodimeric ring-like structure and together with other non-SMC elements form the SMC-5/6 complex. In the worm Caenorhabditis elegans this complex interacts with the HIM-6(BLM) helicase to promote meiotic recombination intermediate processing and chromosome maturation. The SMC-5/6 complex in mouse oocytes is essential for the formation of segregation competent bivalents during meiosis. In the yeast Saccharomyces cerevisiae, SMC6 is necessary for resistance to DNA damage as well as for damage-induced interchromosomal and sister chromatid recombination. In humans, a chromosome breakage syndrome characterized by severe lung disease in early childhood is associated with a mutation in a component of the SMC-5/6 complex. Patient’s cells display chromosome rearrangements, micronuclei, sensitivity to DNA damage and defective homologous recombination.

SMC6 Structural maintenance of chromosomes protein 6 is a protein that in humans is encoded by the SMC6 gene.[1][2] It is involved in the Alternative lengthening of telomeres cancer mechanism.[3] # Role in recombination and meiosis Smc6 and Smc5 proteins form a heterodimeric ring-like structure and together with other non-SMC elements form the SMC-5/6 complex. In the worm Caenorhabditis elegans this complex interacts with the HIM-6(BLM) helicase to promote meiotic recombination intermediate processing and chromosome maturation.[4] The SMC-5/6 complex in mouse oocytes is essential for the formation of segregation competent bivalents during meiosis.[5] In the yeast Saccharomyces cerevisiae, SMC6 is necessary for resistance to DNA damage as well as for damage-induced interchromosomal and sister chromatid recombination.[6] In humans, a chromosome breakage syndrome characterized by severe lung disease in early childhood is associated with a mutation in a component of the SMC-5/6 complex.[7] Patient’s cells display chromosome rearrangements, micronuclei, sensitivity to DNA damage and defective homologous recombination.

https://www.wikidoc.org/index.php/SMC6

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SMG1

SMG1 Serine/threonine-protein kinase SMG1 is an enzyme that in humans is encoded by the SMG1 gene. SMG1 belongs to the phosphatidylinositol 3-kinase-related kinase protein family. # Function This gene encodes a protein involved in nonsense-mediated mRNA decay (NMD) as part of the mRNA surveillance complex. The protein has kinase activity and is thought to function in NMD by phosphorylating the regulator of nonsense transcripts 1 protein. Alternative spliced transcript variants have been described, but their full-length natures have not been determined. # Interactions SMG1 (gene) has been shown to interact with PRKCI and UPF1.

SMG1 Serine/threonine-protein kinase SMG1 is an enzyme that in humans is encoded by the SMG1 gene.[1][2][3][4] SMG1 belongs to the phosphatidylinositol 3-kinase-related kinase protein family. # Function This gene encodes a protein involved in nonsense-mediated mRNA decay (NMD) as part of the mRNA surveillance complex. The protein has kinase activity and is thought to function in NMD by phosphorylating the regulator of nonsense transcripts 1 protein. Alternative spliced transcript variants have been described, but their full-length natures have not been determined.[4] # Interactions SMG1 (gene) has been shown to interact with PRKCI[5] and UPF1.[6]

https://www.wikidoc.org/index.php/SMG1

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SMG6

SMG6 Telomerase-binding protein EST1A is an enzyme that in humans is encoded by the SMG6 gene on chromosome 17. It is ubiquitously expressed in many tissues and cell types. The C-terminus of the EST1A protein contains a PilT N-terminus (PIN) domain. This structure for this domain has been determined by X-ray crystallography. SMG6 functions to bind single-stranded DNA in telomere maintenance and single-stranded RNA in nonsense-mediated mRNA decay (NMD). The SMG6 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease. # Structure ## Gene The SMG6 gene resides on chromosome 17 at the band 17p13.3 and contains 30 exons. This gene produces 3 isoforms through alternative splicing. ## Protein SMG6 is one of three human homologs for Est1p found in Saccharomyces cerevisiae. It contains a PIN domain, which is characteristic of proteins with ribonuclease activity. The PIN domain forms an alpha/beta fold structure that similar to that found in 5' nucleases. Within the PIN domain is a canonical triad of acidic residues that functions to cleave single-stranded RNA. SMG6 also shares a phosphoserine-binding domain resembling the one in 14–3–3 proteins with its other two homologs, SMG5 and SMG7. This 14–3–3-like domain and a C-terminal helical hairpins domain with seven α-helices stacked perpendicular to the 14–3–3-like domain together form a monomeric tetratricopeptide region (TPR). Differences in the orientation and specific residues in the TPR between SMG6 and its homologs may account for why SMG6 does not form a complex with SMG5 and SMG7 when recruited by UPF1. # Function SMG6 is broadly expressed in all human tissues. It has dual functions in telomere maintenance and RNA surveillance pathways. SMG6 binds single-stranded telomere DNA and cooperates with telomerase reverse transcriptase to lengthen telomeres. Overexpression of SMG6 induces anaphase bridges due to chromosome-end fusions and, thus, affects telomere capping, which may directly induce an apoptotic response. SMG6 also functions as an endonuclease in the NMD pathway. The catalytic activity of SMG6 resides in its PIN domain, which is required for the degradation of premature translation termination codons (PTC)-containing mRNAs in human cells. SMG6 cleaves mRNA near the premature translocation-termination codons and requires UPF1 and SMG1 to reduce reporter mRNA levels. # Clinical significance In humans, selected genomic regions based on 150 SNPs were identified in a genome-wide association study (GWAS) on coronary artery disease. Accordingly, the association between recent smoking and the CpG sites within and near these coronary artery disease-related genes were investigated in 724 Caucasian subjects from the Rotterdam Study. The identified methylation sites were found in SMG6 together with other genes, and several of these sites exhibited lower methylation in subjects currently smoking compared to never smoking. ## Clinical marker A multi-locus genetic risk score study based on a combination of 27 loci, including the SMG6 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).

SMG6 Telomerase-binding protein EST1A is an enzyme that in humans is encoded by the SMG6 gene on chromosome 17.[1][2][3] It is ubiquitously expressed in many tissues and cell types.[4] The C-terminus of the EST1A protein contains a PilT N-terminus (PIN) domain. This structure for this domain has been determined by X-ray crystallography.[5] SMG6 functions to bind single-stranded DNA in telomere maintenance and single-stranded RNA in nonsense-mediated mRNA decay (NMD).[6][7] The SMG6 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.[8] # Structure ## Gene The SMG6 gene resides on chromosome 17 at the band 17p13.3 and contains 30 exons.[9] This gene produces 3 isoforms through alternative splicing.[10] ## Protein SMG6 is one of three human homologs for Est1p found in Saccharomyces cerevisiae. It contains a PIN domain, which is characteristic of proteins with ribonuclease activity.[11] The PIN domain forms an alpha/beta fold structure that similar to that found in 5' nucleases.[12] Within the PIN domain is a canonical triad of acidic residues that functions to cleave single-stranded RNA.[13] SMG6 also shares a phosphoserine-binding domain resembling the one in 14–3–3 proteins with its other two homologs, SMG5 and SMG7. This 14–3–3-like domain and a C-terminal helical hairpins domain with seven α-helices stacked perpendicular to the 14–3–3-like domain together form a monomeric tetratricopeptide region (TPR). Differences in the orientation and specific residues in the TPR between SMG6 and its homologs may account for why SMG6 does not form a complex with SMG5 and SMG7 when recruited by UPF1.[14] # Function SMG6 is broadly expressed in all human tissues. It has dual functions in telomere maintenance and RNA surveillance pathways. SMG6 binds single-stranded telomere DNA and cooperates with telomerase reverse transcriptase to lengthen telomeres.[2] Overexpression of SMG6 induces anaphase bridges due to chromosome-end fusions and, thus, affects telomere capping, which may directly induce an apoptotic response.[15][1] SMG6 also functions as an endonuclease in the NMD pathway. The catalytic activity of SMG6 resides in its PIN domain, which is required for the degradation of premature translation termination codons (PTC)-containing mRNAs in human cells.[16] SMG6 cleaves mRNA near the premature translocation-termination codons and requires UPF1 and SMG1 to reduce reporter mRNA levels.[17] # Clinical significance In humans, selected genomic regions based on 150 SNPs were identified in a genome-wide association study (GWAS) on coronary artery disease. Accordingly, the association between recent smoking and the CpG sites within and near these coronary artery disease-related genes were investigated in 724 Caucasian subjects from the Rotterdam Study. The identified methylation sites were found in SMG6 together with other genes, and several of these sites exhibited lower methylation in subjects currently smoking compared to never smoking.[18] ## Clinical marker A multi-locus genetic risk score study based on a combination of 27 loci, including the SMG6 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).[8]

https://www.wikidoc.org/index.php/SMG6

ebf517ac471a73b18e1bfa1f33582412352ada9f

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SMN1

SMN1 Survival of motor neuron 1 (SMN1), also known as component of gems 1 or GEMIN1, is a gene that encodes the SMN protein in humans. # Gene SMN1 is the telomeric copy of the gene encoding the SMN protein; the centromeric copy is termed SMN2. SMN1 and SMN2 are part of a 500 kb inverted duplication on chromosome 5q13. This duplicated region contains at least four genes and repetitive elements which make it prone to rearrangements and deletions. The repetitiveness and complexity of the sequence have also caused difficulty in determining the organization of this genomic region. SMN1 and SMN2 are nearly identical and encode the same protein. The critical sequence difference between the two is a single nucleotide in exon 7 which is thought to be an exon splice enhancer. It is thought that gene conversion events may involve the two genes, leading to varying copy numbers of each gene. # Clinical significance Mutations in SMN1 are associated with spinal muscular atrophy. Mutations in SMN2 alone do not lead to disease, although mutations in both SMN1 and SMN2 result in embryonic death.

SMN1 Survival of motor neuron 1 (SMN1), also known as component of gems 1 or GEMIN1, is a gene that encodes the SMN protein in humans.[1][2] # Gene SMN1 is the telomeric copy of the gene encoding the SMN protein; the centromeric copy is termed SMN2. SMN1 and SMN2 are part of a 500 kb inverted duplication on chromosome 5q13. This duplicated region contains at least four genes and repetitive elements which make it prone to rearrangements and deletions. The repetitiveness and complexity of the sequence have also caused difficulty in determining the organization of this genomic region. SMN1 and SMN2 are nearly identical and encode the same protein.[2] The critical sequence difference between the two is a single nucleotide in exon 7 which is thought to be an exon splice enhancer. It is thought that gene conversion events may involve the two genes, leading to varying copy numbers of each gene.[2] # Clinical significance Mutations in SMN1 are associated with spinal muscular atrophy. Mutations in SMN2 alone do not lead to disease, although mutations in both SMN1 and SMN2 result in embryonic death.

https://www.wikidoc.org/index.php/SMN1

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SMN2

SMN2 Survival of motor neuron 2 (SMN2) is a gene that encodes the SMN protein (full and truncated) in humans. # Gene The SMN2 gene is part of a 500 kb inverted duplication on chromosome 5q13. This duplicated region contains at least four genes and repetitive elements which make it prone to rearrangements and deletions. The repetitiveness and complexity of the sequence have also caused difficulty in determining the organization of this genomic region. The telomeric (SMN1) and centromeric (SMN2) copies of this gene are nearly identical and encode the same protein. The critical sequence difference between the two genes is a single nucleotide in exon 7, which is thought to be an exon splice enhancer. The nucleotide substitution in SMN2 results in around 80-90% of its transcripts to be a truncated, unstable protein of no biological function (Δ7SMN) and only 10-20% of its transcripts being full-length protein (fl-SMN). Note that the nine exons of both the telomeric and centromeric copies are designated historically as exon 1, 2a, 2b, and 3-8. It is thought that gene conversion events may involve the two genes, leading to varying copy numbers of each gene. # Clinical significance While mutations in the telomeric copy are associated with spinal muscular atrophy, mutations in this gene, the centromeric copy, do not lead to disease. This gene may be a modifier of disease caused by mutation in the telomeric copy.

SMN2 Survival of motor neuron 2 (SMN2) is a gene that encodes the SMN protein (full and truncated) in humans.[1][2] # Gene The SMN2 gene is part of a 500 kb inverted duplication on chromosome 5q13. This duplicated region contains at least four genes and repetitive elements which make it prone to rearrangements and deletions. The repetitiveness and complexity of the sequence have also caused difficulty in determining the organization of this genomic region. The telomeric (SMN1) and centromeric (SMN2) copies of this gene are nearly identical and encode the same protein. The critical sequence difference between the two genes is a single nucleotide in exon 7, which is thought to be an exon splice enhancer. The nucleotide substitution in SMN2 results in around 80-90% of its transcripts to be a truncated, unstable protein of no biological function (Δ7SMN) and only 10-20% of its transcripts being full-length protein (fl-SMN). Note that the nine exons of both the telomeric and centromeric copies are designated historically as exon 1, 2a, 2b, and 3-8. It is thought that gene conversion events may involve the two genes, leading to varying copy numbers of each gene.[2] # Clinical significance While mutations in the telomeric copy are associated with spinal muscular atrophy, mutations in this gene, the centromeric copy, do not lead to disease. This gene may be a modifier of disease caused by mutation in the telomeric copy.

https://www.wikidoc.org/index.php/SMN2

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SNF8

SNF8 Vacuolar-sorting protein SNF8 is a protein that in humans is encoded by the SNF8 gene. # Model organisms Model organisms have been used in the study of SNF8 function. A conditional knockout mouse line, called Snf8tm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty five tests were carried out on mutant mice and two significant abnormalities were observed. No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; no additional significant abnormalities were observed in these animals.

SNF8 Vacuolar-sorting protein SNF8 is a protein that in humans is encoded by the SNF8 gene.[1][2][3] # Model organisms Model organisms have been used in the study of SNF8 function. A conditional knockout mouse line, called Snf8tm1a(EUCOMM)Wtsi[8][9] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[10][11][12] Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[6][13] Twenty five tests were carried out on mutant mice and two significant abnormalities were observed.[6] No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; no additional significant abnormalities were observed in these animals.[6]

https://www.wikidoc.org/index.php/SNF8

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SNX5

SNX5 Sorting nexin-5 is a protein that in humans is encoded by the SNX5 gene. This gene encodes a member of the sorting nexin family. Members of this family contain a phox (PX) domain, which is a phosphoinositide binding domain, and are involved in intracellular trafficking. This protein is a component of the mammalian retromer complex, which facilitates cargo retrieval from endosomes to the trans-Golgi network. It has also been shown to bind to the Fanconi anemia, complementation group A protein. This gene results in two transcript variants encoding the same protein. # Model organisms Model organisms have been used in the study of SNX5 function. A conditional knockout mouse line, called Snx5tm1a(KOMP)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty five tests were carried out on homozygous mutant adult mice, however no significant abnormalities were observed. # Interactions SNX5 has been shown to interact with FANCA.

SNX5 Sorting nexin-5 is a protein that in humans is encoded by the SNX5 gene.[1][2][3] This gene encodes a member of the sorting nexin family. Members of this family contain a phox (PX) domain, which is a phosphoinositide binding domain, and are involved in intracellular trafficking. This protein is a component of the mammalian retromer complex,[2] which facilitates cargo retrieval from endosomes to the trans-Golgi network. It has also been shown to bind to the Fanconi anemia, complementation group A protein. This gene results in two transcript variants encoding the same protein.[3] # Model organisms Model organisms have been used in the study of SNX5 function. A conditional knockout mouse line, called Snx5tm1a(KOMP)Wtsi[9][10] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.[11][12][13] Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[7][14] Twenty five tests were carried out on homozygous mutant adult mice, however no significant abnormalities were observed.[7] # Interactions SNX5 has been shown to interact with FANCA.[1]

https://www.wikidoc.org/index.php/SNX5

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SNX9

SNX9 Sorting nexin-9 is a protein that in humans is encoded by the SNX9 gene. This gene encodes a member of the sorting nexin family. Members of this family contain a phox (PX) domain, which is a phosphoinositide binding domain, and are involved in intracellular trafficking. This protein does not contain a coiled coil region, like some family members, but does contain an SH3 domain near its N-terminus. This protein interacts with the cytoplasmic domains of the precursor but not the processed forms of a disintegrin and metalloprotease domain 9 and 15. This protein binds the beta-appendage domain of adaptor protein 2 and may function to assist adaptor protein 2 in its role at the plasma membrane. This protein interacts with activated Cdc42-associated kinase-2 to regulate the degradation of epidermal growth factor receptor protein. # Interactions SNX9 has been shown to interact with ADAM9, DNM2 and ADAM15.

SNX9 Sorting nexin-9 is a protein that in humans is encoded by the SNX9 gene.[1][2][3] This gene encodes a member of the sorting nexin family. Members of this family contain a phox (PX) domain, which is a phosphoinositide binding domain, and are involved in intracellular trafficking. This protein does not contain a coiled coil region, like some family members, but does contain an SH3 domain near its N-terminus. This protein interacts with the cytoplasmic domains of the precursor but not the processed forms of a disintegrin and metalloprotease domain 9 and 15. This protein binds the beta-appendage domain of adaptor protein 2 and may function to assist adaptor protein 2 in its role at the plasma membrane. This protein interacts with activated Cdc42-associated kinase-2 to regulate the degradation of epidermal growth factor receptor protein.[3] # Interactions SNX9 has been shown to interact with ADAM9,[1] DNM2[4] and ADAM15.[1]

https://www.wikidoc.org/index.php/SNX9

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SOAP

SOAP SOAP (see below for name and origins) is a protocol for exchanging XML-based messages over computer networks, normally using HTTP/HTTPS. SOAP forms the foundation layer of the web services protocol stack providing a basic messaging framework upon which abstract layers can be built. As a layman's example of how SOAP procedures can be used, a correctly formatted call could be sent to a Web Service enabled web site - for example, a house price database - with the data ranges needed for a search. The site could then return a formatted XML document with all the required results and associated data (prices, location, features, etc). These could then be integrated directly into a third-party site. There are several different types of messaging patterns in SOAP, but by far the most common is the Remote Procedure Call (RPC) pattern, in which one network node (the client) sends a request message to another node (the server) and the server immediately sends a response message to the client. SOAP is the successor of XML-RPC, though it borrows its transport and interaction neutrality and the envelope/header/body from elsewhere, probably from WDDX. # History SOAP once stood for 'Simple Object Access Protocol' but this acronym was dropped with Version 1.2 of the standard, as it was considered to be misleading. Version 1.2 became a W3C Recommendation on June 24 2003. The acronym is sometimes confused with SOA, or Service-oriented architecture; however SOAP is quite different from SOA. SOAP was originally designed by Dave Winer, Don Box, Bob Atkinson, and Mohsen Al-Ghosein in 1998, with backing from Microsoft (where Atkinson and Al-Ghosein worked at the time), as an object-access protocol. The SOAP specification is currently maintained by the XML Protocol Working Group of the World Wide Web Consortium. # Transport methods SOAP makes use of an Internet application layer protocol as a transport protocol. Critics have argued that this is an abuse of such protocols, as it is not their intended purpose and therefore not a role they fulfill well. Backers of SOAP have drawn analogies to successful uses of protocols at various levels for tunneling other protocols. Both SMTP and HTTP are valid application layer protocols used as Transport for SOAP, but HTTP has gained wider acceptance as it works well with today's Internet infrastructure; specifically, HTTP works well with network firewalls. SOAP may also be used over HTTPS (which is the same protocol as HTTP at the application level, but uses an encrypted transport protocol underneath) in either simple or mutual authentication; this is the advocated WS-I method to provide web service security as stated in the WS-I Basic Profile 1.1. This is a major advantage over other distributed protocols like GIOP/IIOP or DCOM which are normally filtered by firewalls. XML was chosen as the standard message format because of its widespread use by major corporations and open source development efforts. Additionally, a wide variety of freely available tools significantly eases the transition to a SOAP-based implementation.. The somewhat lengthy syntax of XML can be both a benefit and a drawback. While it promotes readability for humans, it can retard processing speed and be cumbersome. For example, CORBA, GIOP, ICE, and DCOM use much shorter, binary message formats. On the other hand, hardware appliances are available to accelerate processing of XML messages. . Binary XML is also being explored as a means for streamlining the throughput requirements of XML. # Technical critique Numerous commentators and specialists have discussed the technical advantages and disadvantages of SOAP relative to alternative technologies, and relative to the context of its intended use. ## Advantages - Using SOAP over HTTP allows for easier communication through proxies and firewalls than previous remote execution technology. - SOAP is versatile enough to allow for the use of different transport protocols. The standard stacks use HTTP as a transport protocol, but other protocols are also usable (e.g. SMTP, RSS). - SOAP is platform independent. - SOAP is language independent. - SOAP is simple and extensible. ## Disadvantages - Because of the verbose XML format, SOAP can be considerably slower than competing middleware technologies such as CORBA. This may not be an issue when only small messages are sent. To improve performance for the special case of XML with embedded binary objects, Message Transmission Optimization Mechanism was introduced. Further, to improve the performance of XML in general, there are emerging non-extractive XML processing models, e.g., VTD-XML. - When relying on HTTP as a transport protocol and not using WS-Addressing or an ESB, the roles of the interacting parties are fixed. Only one party (the client) can use the services of the other. Developers must use polling instead of notification in these common cases. - Most uses of HTTP as a transport protocol are done in ignorance of how the operation would be modelled in HTTP. This is by design (with analogy to how different protocols sit on top of each other in the IP stack) but the analogy is imperfect (because the application protocols used as transport protocols are not really transport protocols). Because of this, there is no way to know if the method used is appropriate to the operation. This makes good analysis of the operation at the application-protocol level problematic at best with results that are sub-optimal (if the POST-based binding is used for an application which in HTTP would be more naturally modelled as a GET operation). # Additional information - SOAP with Attachments - SOAP with Attachments API for Java - SOAP Over JMS Interoperability - Web Services Description Language (WSDL)

SOAP SOAP (see below for name and origins) is a protocol for exchanging XML-based messages over computer networks, normally using HTTP/HTTPS. SOAP forms the foundation layer of the web services protocol stack providing a basic messaging framework upon which abstract layers can be built. As a layman's example of how SOAP procedures can be used, a correctly formatted call could be sent to a Web Service enabled web site - for example, a house price database - with the data ranges needed for a search. The site could then return a formatted XML document with all the required results and associated data (prices, location, features, etc). These could then be integrated directly into a third-party site. There are several different types of messaging patterns in SOAP, but by far the most common is the Remote Procedure Call (RPC) pattern, in which one network node (the client) sends a request message to another node (the server) and the server immediately sends a response message to the client. SOAP is the successor of XML-RPC, though it borrows its transport and interaction neutrality and the envelope/header/body from elsewhere, probably from WDDX.[citation needed] # History SOAP once stood for 'Simple Object Access Protocol' but this acronym was dropped with Version 1.2 of the standard, as it was considered to be misleading. Version 1.2 became a W3C Recommendation on June 24 2003. The acronym is sometimes confused with SOA, or Service-oriented architecture; however SOAP is quite different from SOA. SOAP was originally designed by Dave Winer, Don Box, Bob Atkinson, and Mohsen Al-Ghosein in 1998, with backing from Microsoft (where Atkinson and Al-Ghosein worked at the time), as an object-access protocol. The SOAP specification is currently maintained by the XML Protocol Working Group of the World Wide Web Consortium. # Transport methods SOAP makes use of an Internet application layer protocol as a transport protocol. Critics have argued that this is an abuse of such protocols, as it is not their intended purpose and therefore not a role they fulfill well. Backers of SOAP have drawn analogies to successful uses of protocols at various levels for tunneling other protocols.[citation needed] Both SMTP and HTTP are valid application layer protocols used as Transport for SOAP, but HTTP has gained wider acceptance as it works well with today's Internet infrastructure; specifically, HTTP works well with network firewalls. SOAP may also be used over HTTPS (which is the same protocol as HTTP at the application level, but uses an encrypted transport protocol underneath) in either simple or mutual authentication; this is the advocated WS-I method to provide web service security as stated in the WS-I Basic Profile 1.1. This is a major advantage over other distributed protocols like GIOP/IIOP or DCOM which are normally filtered by firewalls. XML was chosen as the standard message format because of its widespread use by major corporations and open source development efforts. Additionally, a wide variety of freely available tools significantly eases the transition to a SOAP-based implementation.. The somewhat lengthy syntax of XML can be both a benefit and a drawback. While it promotes readability for humans, it can retard processing speed and be cumbersome. For example, CORBA, GIOP, ICE, and DCOM use much shorter, binary message formats. On the other hand, hardware appliances are available to accelerate processing of XML messages. [1][2]. Binary XML is also being explored as a means for streamlining the throughput requirements of XML. # Technical critique Numerous commentators and specialists have discussed the technical advantages and disadvantages of SOAP relative to alternative technologies, and relative to the context of its intended use. ## Advantages - Using SOAP over HTTP allows for easier communication through proxies and firewalls than previous remote execution technology. - SOAP is versatile enough to allow for the use of different transport protocols. The standard stacks use HTTP as a transport protocol, but other protocols are also usable (e.g. SMTP, RSS). - SOAP is platform independent. - SOAP is language independent. - SOAP is simple and extensible. ## Disadvantages - Because of the verbose XML format, SOAP can be considerably slower than competing middleware technologies such as CORBA. This may not be an issue when only small messages are sent[3]. To improve performance for the special case of XML with embedded binary objects, Message Transmission Optimization Mechanism was introduced. Further, to improve the performance of XML in general, there are emerging non-extractive XML processing models, e.g., VTD-XML. - When relying on HTTP as a transport protocol and not using WS-Addressing or an ESB, the roles of the interacting parties are fixed. Only one party (the client) can use the services of the other. Developers must use polling instead of notification in these common cases. - Most uses of HTTP as a transport protocol are done in ignorance of how the operation would be modelled in HTTP. This is by design (with analogy to how different protocols sit on top of each other in the IP stack) but the analogy is imperfect (because the application protocols used as transport protocols are not really transport protocols). Because of this, there is no way to know if the method used is appropriate to the operation. This makes good analysis of the operation at the application-protocol level problematic at best with results that are sub-optimal (if the POST-based binding is used for an application which in HTTP would be more naturally modelled as a GET operation). # Additional information - SOAP with Attachments - SOAP with Attachments API for Java - SOAP Over JMS Interoperability - Web Services Description Language (WSDL) # External Links - W3C SOAP page - SOAP Tutorial Template:WH Template:WS Template:Compu-network-stub ar:سواب bn:সিম্প্‌ল অবজেক্ট এক্সেস প্রোটকল ca:SOAP cs:Simple Object Access Protocol da:SOAP de:SOAP eo:SOAP eu:SOAP fa:پروتکل دسترسی آسان به اشیاء gl:Simple Object Access Protocol ko:SOAP id:SOAP is:SOAP it:SOAP he:SOAP hu:SOAP nl:Simple Object Access Protocol sk:Simple Object Access Protocol fi:SOAP sv:SOAP uk:SOAP

https://www.wikidoc.org/index.php/SOAP

5d53c8fc65c6e3cdddab238ea85e2862aa7b5929

wikidoc

SOD1

SOD1 Superoxide dismutase also known as superoxide dismutase 1 or SOD1 is an enzyme that in humans is encoded by the SOD1 gene, located on chromosome 21. SOD1 is one of three human superoxide dismutases. It is implicated in apoptosis and amyotrophic lateral sclerosis. # Structure SOD1 is a 32 kDa homodimer which forms a β-barrel and contains an intramolecular disulfide bond and a binuclear Cu/Zn site in each subunit. This Cu/Zn site holds the copper and a zinc ion and is responsible for catalyzing the disproportionation of superoxide to hydrogen peroxide and dioxygen. The maturation process of this protein is complex and not fully understood, involving the selective binding of copper and zinc ions, formation of the intra-subunit disulfide bond between Cys-57 and Cys-146, and dimerization of the two subunits. The copper chaperone for Sod1 (CCS) facilitates copper insertion and disulfide oxidation. Though SOD1 is synthesized in the cytosol and can mature there, the fraction of expressed, and still immature, SOD1 targeted to the mitochondria must be inserted into the intermembrane space. There, it forms the disulfide bond, though not metalation, required for its maturation. The mature protein is highly stable, but unstable when in its metal-free and disulfide-reduced forms. This manifests in vitro, as the loss of metal ions results in increased SOD1 aggregation, and in disease models, where low metalation is observed for insoluble SOD1. Moreover, the surface-exposed reduced cysteines could participate in disulfide crosslinking and, thus, aggregation. # Function SOD1 binds copper and zinc ions and is one of three superoxide dismutases responsible for destroying free superoxide radicals in the body. The encoded isozyme is a soluble cytoplasmic and mitochondrial intermembrane space protein, acting as a homodimer to convert naturally occurring, but harmful, superoxide radicals to molecular oxygen and hydrogen peroxide. Hydrogen peroxide can then be broken down by another enzyme called catalase. SOD1 has been postulated to localize to the outer mitochondrial membrane (OMM), where superoxide anions would be generated, or the intermembrane space. The exact mechanisms for its localization remains unknown, but its aggregation to the OMM has been attributed to its association with BCL-2. Wildtype SOD1 has demonstrated antiapoptotic properties in neural cultures, while mutant SOD1 has been observed to promote apoptosis in spinal cord mitochondria, but not in liver mitochondria, though it is equally expressed in both. Two models suggest SOD1 inhibits apoptosis by interacting with BCL-2 proteins or the mitochondria itself. # Clinical significance ## Role in oxidative stress Most notably, SOD1 is pivotal in reactive oxygen species (ROS) release during oxidative stress by ischemia-reperfusion injury, specifically in the myocardium as part of a heart attack (also known as ischemic heart disease). Ischemic heart disease, which results from an occlusion of one of the major coronary arteries, is currently still the leading cause of morbidity and mortality in western society. During ischemia reperfusion, ROS release substantially contribute to the cell damage and death via a direct effect on the cell as well as via apoptotic signals. SOD1 is known to have a capacity to limit the detrimental effects of ROS. As such, SOD1 is important for its cardioprotective effects. In addition, SOD1 has been implicated in cardioprotection against ischemia-reperfusion injury, such as during ischemic preconditioning of the heart. Although a large burst of ROS is known to lead to cell damage, a moderate release of ROS from the mitochondria, which occurs during nonlethal short episodes of ischemia, can play a significant triggering role in the signal transduction pathways of ischemic preconditioning leading to reduction of cell damage. It has even observed that during this release of ROS, SOD1 plays an important role hereby regulating apoptotic signaling and cell death. In one study, deletions in the gene were reported in two familial cases of keratoconus. Mice lacking SOD1 have increased age-related muscle mass loss (sarcopenia), early development of cataracts, macular degeneration, thymic involution, hepatocellular carcinoma, and shortened lifespan. Research suggests that increased SOD1 levels could be a biomarker for chronic heavy metal toxicity in women with long-term dental amalgam fillings. ## Amyotrophic lateral sclerosis (Lou Gehrig's disease) Mutations (over 150 identified to date) in this gene have been linked to familial amyotrophic lateral sclerosis. However, several pieces of evidence also show that wild-type SOD1, under conditions of cellular stress, is implicated in a significant fraction of sporadic ALS cases, which represent 90% of ALS patients. The most frequent mutation are A4V (in the U.S.A.) and H46R (Japan). In Iceland only SOD1-G93S has been found. The most studied ALS mouse model is G93A. Rare transcript variants have been reported for this gene. Virtually all known ALS-causing SOD1 mutations act in a dominant fashion; a single mutant copy of the SOD1 gene is sufficient to cause the disease. The exact molecular mechanism (or mechanisms) by which SOD1 mutations cause disease are unknown. It appears to be some sort of toxic gain of function, as many disease-associated SOD1 mutants (including G93A and A4V) retain enzymatic activity and Sod1 knockout mice do not develop ALS (although they do exhibit a strong age-dependent distal motor neuropathy). ALS is a neurodegenerative disease characterized by selective loss of motor neurons causing muscle atrophy. The DNA oxidation product 8-OHdG is a well-established marker of oxidative DNA damage. 8-OHdG accumulates in the mitochondria of spinal motor neurons of persons with ALS. In transgenic ALS mice harboring a mutant SOD1 gene, 8-OHdG also accumulates in mitochondrial DNA of spinal motor neurons. These findings suggest that oxidative damage to mitochondrial DNA of motor neurons due to altered SOD1 may be significant factor in the etiology of ALS. ### A4V mutation A4V (alanine at codon 4 changed to valine) is the most common ALS-causing mutation in the U.S. population, with approximately 50% of SOD1-ALS patients carrying the A4V mutation. Approximately 10 percent of all U.S. familial ALS cases are caused by heterozygous A4V mutations in SOD1. The mutation is rarely if ever found outside the Americas. It was recently estimated that the A4V mutation occurred 540 generations (~12,000 years) ago. The haplotype surrounding the mutation suggests that the A4V mutation arose in the Asian ancestors of Native Americans, who reached the Americas through the Bering Strait. The A4V mutant belongs to the WT-like mutants. Patients with A4V mutations exhibit variable age of onset, but uniformly very rapid disease course, with average survival after onset of 1.4 years (versus 3–5 years with other dominant SOD1 mutations, and in some cases such as H46R, considerably longer). This survival is considerably shorter than non-mutant SOD1 linked ALS. ### H46R mutation H46R (histidine at codon 46 changed to arginine) is the most common ALS-causing mutation in the Japanese population, with about 40% of Japanese SOD1-ALS patients carrying this mutation. H46R causes a profound loss of copper binding in the active site of SOD1, and as such, H46R is enzymatically inactive. The disease course of this mutation is extremely long, with the typical time from onset to death being over 15 years. Mouse models with this mutation do not exhibit the classical mitochondrial vacuolation pathology seen in G93A and G37R ALS mice and unlike G93A mice, defeciency of the major mitochondrial antioxidant enzyme, SOD2, has no effect on their disease course. ### G93A mutation G93A (glycine 93 changed to alanine) is a comparatively rare mutation, but has been studied very intensely as it was the first mutation to be modeled in mice. G93A is a pseudo-WT mutation that leaves the enzyme activity intact. Because of the ready availability of the G93A mouse from Jackson Laboratory, many studies of potential drug targets and toxicity mechanisms have been carried out in this model. At least one private research institute (ALS Therapy Development Institute) is conducting large-scale drug screens exclusively in this mouse model. Whether findings are specific for G93A or applicable to all ALS causing SOD1 mutations is at present unknown. It has been argued that certain pathological features of the G93A mouse are due to overexpression artefacts, specifically those relating to mitochondrial vacuolation (the G93A mouse commonly used from Jackson Lab has over 20 copies of the human SOD1 gene). At least one study has found that certain features of pathology are idiosyncratic to G93A and not extrapolatable to all ALS-causing mutations. Further studies have shown that the pathogenesis of the G93A and H46R models are clearly distinct; some drugs and genetic interventions that are highly beneficial/detrimental in one model have either the opposite or no effect in the other. ## Down syndrome Down syndrome (DS) is caused by a triplication of chromosome 21. Oxidative stress is thought be an important underlying factor in DS-related pathologies. The oxidative stress appears to be due to the triplication and increased expression of the SOD1 gene located in chromosome 21. Increased expression of SOD1 likely causes increased production of hydrogen peroxide leading to increased cellular injury. The levels of 8-OHdG in the DNA of persons with DS, measured in saliva, were found to be significantly higher than in control groups. 8-OHdG levels were also increased in the leukocytes of persons with DS compared to controls. These findings suggest that oxidative DNA damage may lead to some of the clinical features of DS. # Interactions SOD1 has been shown to interact with CCS and Bcl-2.

SOD1 Superoxide dismutase [Cu-Zn] also known as superoxide dismutase 1 or SOD1 is an enzyme that in humans is encoded by the SOD1 gene, located on chromosome 21. SOD1 is one of three human superoxide dismutases.[1][2] It is implicated in apoptosis and amyotrophic lateral sclerosis.[2] # Structure SOD1 is a 32 kDa homodimer which forms a β-barrel and contains an intramolecular disulfide bond and a binuclear Cu/Zn site in each subunit. This Cu/Zn site holds the copper and a zinc ion and is responsible for catalyzing the disproportionation of superoxide to hydrogen peroxide and dioxygen.[3][4] The maturation process of this protein is complex and not fully understood, involving the selective binding of copper and zinc ions, formation of the intra-subunit disulfide bond between Cys-57 and Cys-146, and dimerization of the two subunits. The copper chaperone for Sod1 (CCS) facilitates copper insertion and disulfide oxidation. Though SOD1 is synthesized in the cytosol and can mature there, the fraction of expressed, and still immature, SOD1 targeted to the mitochondria must be inserted into the intermembrane space. There, it forms the disulfide bond, though not metalation, required for its maturation.[4] The mature protein is highly stable,[5] but unstable when in its metal-free and disulfide-reduced forms.[3][4][5] This manifests in vitro, as the loss of metal ions results in increased SOD1 aggregation, and in disease models, where low metalation is observed for insoluble SOD1. Moreover, the surface-exposed reduced cysteines could participate in disulfide crosslinking and, thus, aggregation.[3] # Function SOD1 binds copper and zinc ions and is one of three superoxide dismutases responsible for destroying free superoxide radicals in the body. The encoded isozyme is a soluble cytoplasmic and mitochondrial intermembrane space protein, acting as a homodimer to convert naturally occurring, but harmful, superoxide radicals to molecular oxygen and hydrogen peroxide.[4][6] Hydrogen peroxide can then be broken down by another enzyme called catalase. SOD1 has been postulated to localize to the outer mitochondrial membrane (OMM), where superoxide anions would be generated, or the intermembrane space. The exact mechanisms for its localization remains unknown, but its aggregation to the OMM has been attributed to its association with BCL-2. Wildtype SOD1 has demonstrated antiapoptotic properties in neural cultures, while mutant SOD1 has been observed to promote apoptosis in spinal cord mitochondria, but not in liver mitochondria, though it is equally expressed in both. Two models suggest SOD1 inhibits apoptosis by interacting with BCL-2 proteins or the mitochondria itself.[2] # Clinical significance ## Role in oxidative stress Most notably, SOD1 is pivotal in reactive oxygen species (ROS) release during oxidative stress by ischemia-reperfusion injury, specifically in the myocardium as part of a heart attack (also known as ischemic heart disease). Ischemic heart disease, which results from an occlusion of one of the major coronary arteries, is currently still the leading cause of morbidity and mortality in western society.[7][8] During ischemia reperfusion, ROS release substantially contribute to the cell damage and death via a direct effect on the cell as well as via apoptotic signals. SOD1 is known to have a capacity to limit the detrimental effects of ROS. As such, SOD1 is important for its cardioprotective effects.[9] In addition, SOD1 has been implicated in cardioprotection against ischemia-reperfusion injury, such as during ischemic preconditioning of the heart.[10] Although a large burst of ROS is known to lead to cell damage, a moderate release of ROS from the mitochondria, which occurs during nonlethal short episodes of ischemia, can play a significant triggering role in the signal transduction pathways of ischemic preconditioning leading to reduction of cell damage. It has even observed that during this release of ROS, SOD1 plays an important role hereby regulating apoptotic signaling and cell death. In one study, deletions in the gene were reported in two familial cases of keratoconus.[11] Mice lacking SOD1 have increased age-related muscle mass loss (sarcopenia), early development of cataracts, macular degeneration, thymic involution, hepatocellular carcinoma, and shortened lifespan.[12] Research suggests that increased SOD1 levels could be a biomarker for chronic heavy metal toxicity in women with long-term dental amalgam fillings.[13] ## Amyotrophic lateral sclerosis (Lou Gehrig's disease) Mutations (over 150 identified to date) in this gene have been linked to familial amyotrophic lateral sclerosis.[14][15][16] However, several pieces of evidence also show that wild-type SOD1, under conditions of cellular stress, is implicated in a significant fraction of sporadic ALS cases, which represent 90% of ALS patients.[17] The most frequent mutation are A4V (in the U.S.A.) and H46R (Japan). In Iceland only SOD1-G93S has been found. The most studied ALS mouse model is G93A. Rare transcript variants have been reported for this gene.[6] Virtually all known ALS-causing SOD1 mutations act in a dominant fashion; a single mutant copy of the SOD1 gene is sufficient to cause the disease. The exact molecular mechanism (or mechanisms) by which SOD1 mutations cause disease are unknown. It appears to be some sort of toxic gain of function,[16] as many disease-associated SOD1 mutants (including G93A and A4V) retain enzymatic activity and Sod1 knockout mice do not develop ALS (although they do exhibit a strong age-dependent distal motor neuropathy). ALS is a neurodegenerative disease characterized by selective loss of motor neurons causing muscle atrophy. The DNA oxidation product 8-OHdG is a well-established marker of oxidative DNA damage. 8-OHdG accumulates in the mitochondria of spinal motor neurons of persons with ALS.[18] In transgenic ALS mice harboring a mutant SOD1 gene, 8-OHdG also accumulates in mitochondrial DNA of spinal motor neurons.[19] These findings suggest that oxidative damage to mitochondrial DNA of motor neurons due to altered SOD1 may be significant factor in the etiology of ALS. ### A4V mutation A4V (alanine at codon 4 changed to valine) is the most common ALS-causing mutation in the U.S. population, with approximately 50% of SOD1-ALS patients carrying the A4V mutation.[20][21][22] Approximately 10 percent of all U.S. familial ALS cases are caused by heterozygous A4V mutations in SOD1. The mutation is rarely if ever found outside the Americas. It was recently estimated that the A4V mutation occurred 540 generations (~12,000 years) ago. The haplotype surrounding the mutation suggests that the A4V mutation arose in the Asian ancestors of Native Americans, who reached the Americas through the Bering Strait.[23] The A4V mutant belongs to the WT-like mutants. Patients with A4V mutations exhibit variable age of onset, but uniformly very rapid disease course, with average survival after onset of 1.4 years (versus 3–5 years with other dominant SOD1 mutations, and in some cases such as H46R, considerably longer). This survival is considerably shorter than non-mutant SOD1 linked ALS. ### H46R mutation H46R (histidine at codon 46 changed to arginine) is the most common ALS-causing mutation in the Japanese population, with about 40% of Japanese SOD1-ALS patients carrying this mutation. H46R causes a profound loss of copper binding in the active site of SOD1, and as such, H46R is enzymatically inactive. The disease course of this mutation is extremely long, with the typical time from onset to death being over 15 years.[24] Mouse models with this mutation do not exhibit the classical mitochondrial vacuolation pathology seen in G93A and G37R ALS mice and unlike G93A mice, defeciency of the major mitochondrial antioxidant enzyme, SOD2, has no effect on their disease course.[24] ### G93A mutation G93A (glycine 93 changed to alanine) is a comparatively rare mutation, but has been studied very intensely as it was the first mutation to be modeled in mice. G93A is a pseudo-WT mutation that leaves the enzyme activity intact.[22] Because of the ready availability of the G93A mouse from Jackson Laboratory, many studies of potential drug targets and toxicity mechanisms have been carried out in this model. At least one private research institute (ALS Therapy Development Institute) is conducting large-scale drug screens exclusively in this mouse model. Whether findings are specific for G93A or applicable to all ALS causing SOD1 mutations is at present unknown. It has been argued that certain pathological features of the G93A mouse are due to overexpression artefacts, specifically those relating to mitochondrial vacuolation (the G93A mouse commonly used from Jackson Lab has over 20 copies of the human SOD1 gene).[25] At least one study has found that certain features of pathology are idiosyncratic to G93A and not extrapolatable to all ALS-causing mutations.[24] Further studies have shown that the pathogenesis of the G93A and H46R models are clearly distinct; some drugs and genetic interventions that are highly beneficial/detrimental in one model have either the opposite or no effect in the other.[26][27][28] ## Down syndrome Down syndrome (DS) is caused by a triplication of chromosome 21. Oxidative stress is thought be an important underlying factor in DS-related pathologies. The oxidative stress appears to be due to the triplication and increased expression of the SOD1 gene located in chromosome 21. Increased expression of SOD1 likely causes increased production of hydrogen peroxide leading to increased cellular injury. The levels of 8-OHdG in the DNA of persons with DS, measured in saliva, were found to be significantly higher than in control groups.[29] 8-OHdG levels were also increased in the leukocytes of persons with DS compared to controls.[30] These findings suggest that oxidative DNA damage may lead to some of the clinical features of DS. # Interactions SOD1 has been shown to interact with CCS[31] and Bcl-2.[32][33][34][35]

https://www.wikidoc.org/index.php/SOD1

3d9cc6ee6c1e0f6edaeed92f4862d3f586545407

wikidoc

SOD2

SOD2 Superoxide dismutase 2, mitochondrial (SOD2), also known as manganese-dependent superoxide dismutase (MnSOD), is an enzyme which in humans is encoded by the SOD2 gene on chromosome 6. A related pseudogene has been identified on chromosome 1. Alternative splicing of this gene results in multiple transcript variants. This gene is a member of the iron/manganese superoxide dismutase family. It encodes a mitochondrial protein that forms a homotetramer and binds one manganese ion per subunit. This protein binds to the superoxide byproducts of oxidative phosphorylation and converts them to hydrogen peroxide and diatomic oxygen. Mutations in this gene have been associated with idiopathic cardiomyopathy (IDC), premature aging, sporadic motor neuron disease, and cancer. # Structure The SOD2 gene contains five exons interrupted by four introns, an uncharacteristic 5′-proximal promoter that possesses a GC-rich region in place of the TATA or CAAT, and an enhancer in the second intron. The proximal promoter region contains multiple binding sites for transcription factors, including specific-1 (Sp1), activator protein 2 (AP-2), and early growth response 1 (Egr-1). This gene is a mitochondrial member of the iron/manganese superoxide dismutase family. It encodes a mitochondrial matrix protein that forms a homotetramer and binds one manganese ion per subunit. The manganese site forms a trigonal bipyramidal geometry with four ligands from the protein and a fifth solvent ligand. This solvent ligand is a hydroxide believed to serve as the electron acceptor of the enzyme. The active site cavity consists of a network of side chains of several residues associated by hydrogen bonding, extending from the aqueous ligand of the metal. Of note, the highly conserved residue Tyr34 plays a key role in the hydrogen-bonding network, as nitration of this residue inhibits the protein's catalytic ability. This protein also possesses an N-terminal mitochondrial leader sequence which targets it to the mitochondrial matrix, where it converts mitochondrial-generated reactive oxygen species from the respiratory chain to H2. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. # Function As a member of the iron/manganese superoxide dismutase family, this protein transforms toxic superoxide, a byproduct of the mitochondrial electron transport chain, into hydrogen peroxide and diatomic oxygen. This function allows SOD2 to clear mitochondrial reactive oxygen species (ROS) and, as a result, confer protection against cell death. As a result, this protein plays an antiapoptotic role against oxidative stress, ionizing radiation, and inflammatory cytokines. # Clinical significance The SOD2 enzyme is an important constituent in apoptotic signaling and oxidative stress, most notably as part of the mitochondrial death pathway and cardiac myocyte apoptosis signaling. Programmed cell death is a distinct genetic and biochemical pathway essential to metazoans. An intact death pathway is required for successful embryonic development and the maintenance of normal tissue homeostasis. Apoptosis has proven to be tightly interwoven with other essential cell pathways. The identification of critical control points in the cell death pathway has yielded fundamental insights for basic biology, as well as provided rational targets for new therapeutics a normal embryologic processes, or during cell injury (such as ischemia-reperfusion injury during heart attacks and strokes) or during developments and processes in cancer, an apoptotic cell undergoes structural changes including cell shrinkage, plasma membrane blebbing, nuclear condensation, and fragmentation of the DNA and nucleus. This is followed by fragmentation into apoptotic bodies that are quickly removed by phagocytes, thereby preventing an inflammatory response. It is a mode of cell death defined by characteristic morphological, biochemical and molecular changes. It was first described as a "shrinkage necrosis", and then this term was replaced by apoptosis to emphasize its role opposite mitosis in tissue kinetics. In later stages of apoptosis the entire cell becomes fragmented, forming a number of plasma membrane-bounded apoptotic bodies which contain nuclear and or cytoplasmic elements. The ultrastructural appearance of necrosis is quite different, the main features being mitochondrial swelling, plasma membrane breakdown and cellular disintegration. Apoptosis occurs in many physiological and pathological processes. It plays an important role during embryonal development as programmed cell death and accompanies a variety of normal involutional processes in which it serves as a mechanism to remove "unwanted" cells. ## Role in oxidative stress Most notably, SOD2 is pivotal in reactive oxygen species (ROS) release during oxidative stress by ischemia-reperfusion injury, specifically in the myocardium as part of a heart attack (also known as ischemic heart disease). Ischemic heart disease, which results from an occlusion of one of the major coronary arteries, is currently still the leading cause of morbidity and mortality in western society. During ischemia reperfusion, ROS release substantially contribute to the cell damage and death via a direct effect on the cell as well as via apoptotic signals. SOD2 is known to have a capacity to limit the detrimental effects of ROS. As such, SOD2 is important for its cardioprotective effects. In addition, SOD2 has been implicated in cardioprotection against ischemia-reperfusion injury, such as during ischemic preconditioning of the heart. Although a large burst of ROS is known to lead to cell damage, a moderate release of ROS from the mitochondria, which occurs during nonlethal short episodes of ischemia, can play a significant triggering role in the signal transduction pathways of ischemic preconditioning leading to reduction of cell damage. It has even observed that during this release of ROS, SOD2 plays an important role hereby regulating apoptotic signaling and cell death. Due to its cytoprotective effects, overexpression of SOD2 has been linked to increased invasiveness of tumor metastasis. Its role in controlling ROS levels also involves it in ageing, cancer, and neurodegenerative disease. Mutations in this gene have been associated with idiopathic cardiomyopathy (IDC), sporadic motor neuron disease, and cancer. A common polymorphism associated with greater susceptibility to various pathologies is found in the mitochondrial leader targeting sequence (Val9Ala). Mice lacking Sod2 die shortly after birth, indicating that unchecked levels of superoxide are incompatible with mammalian life. However, mice 50% deficient in Sod2 have a normal lifespan and minimal phenotypic defects but do suffer increased DNA damage and increased incidence of cancer. In Drosophila melanogaster, over-expression of Sod2 has been show to increase lifespan by 20%. # Role in Invertebrates SOD2's significant role in oxidative stress management makes it an essential component of the mitochondria. As a result, SOD2 similarly to SOD1 and SOD3 is highly conserved in vertebrates as well as invertebrates (organisms that do not possess a vertebral column). In the study Multiple measures of functionality exhibit progressive decline in a parallel, stochastic fashion in Drosophilla Sod2 mutants. In SOD2 mutants there was a cascade of deterioration within the organ systems. These deterioration were not linear in that one organs system would fail then the other, rather on the contrary the deterioration were parallel, meaning that various systems would be affected at any given time. The build up of ROS's in the flies did play a substantial role in affecting the organ system s of the flies in such a way, that though not all observed flies suffered permanent damage, the damages that were observed were like those associated with old age in mature fruit flies. The tissues that are affected in light of defective SOD2 in invertebrates are the muscles, heart, brain and behavior. ROS's effect on these tissue results in not only loss of cellular function in most cases, but a substantial loss in longevity. Though SOD2's role in oxidative stress management is one that has been accepted for both vertebrates and invertebrates, it's necessity has been question by a study that was conducted on Caenorhabditis elegans (C. elegans). The correlation between the lack of/ defective SOD2 and loss of longevity and function is generally understood, however it was discovered that the removal of some of the five members of the SOD family including SOD2 resulted in the increase in longevity in mutant C. elegans compared to the wild type. # Animal studies When animals are exercised at a relatively high work rate, exercise training promotes an increase in myocardial MnSOD activity. Increased MnSOD activity is required to achieve optimal training-induced protection against both ischemia/reperfusion(IR)-induced cardiac arrhythmias and infarction Using an antisense oligonucleotide against MnSOD to prevent ExTr-induced increases in myocardial MnSOD activity, it was demonstrated that an increase in myocardial MnSOD activity is required to provide training-induced protection against IR-induced myocardial infarction. Using a MnSOD gene silencing approach, reported that prevention of the ExTr-induced increase in myocardial MnSOD resulted in a loss of training-induced protection against IR-mediated arrhythmias. # Interactions The SOD2 gene has been shown to bind: - Sp1, - NF-κB, - AP-1, - AP-2, - Egr-1, - CREB, - p53, and - NFE2L2. The SOD2 protein has been shown to interact with HIV-1 Tat and HIV-1 Vif.

SOD2 Superoxide dismutase 2, mitochondrial (SOD2), also known as manganese-dependent superoxide dismutase (MnSOD), is an enzyme which in humans is encoded by the SOD2 gene on chromosome 6.[1][2] A related pseudogene has been identified on chromosome 1. Alternative splicing of this gene results in multiple transcript variants.[1] This gene is a member of the iron/manganese superoxide dismutase family. It encodes a mitochondrial protein that forms a homotetramer and binds one manganese ion per subunit. This protein binds to the superoxide byproducts of oxidative phosphorylation and converts them to hydrogen peroxide and diatomic oxygen. Mutations in this gene have been associated with idiopathic cardiomyopathy (IDC), premature aging, sporadic motor neuron disease, and cancer.[1] # Structure The SOD2 gene contains five exons interrupted by four introns, an uncharacteristic 5′-proximal promoter that possesses a GC-rich region in place of the TATA or CAAT, and an enhancer in the second intron. The proximal promoter region contains multiple binding sites for transcription factors, including specific-1 (Sp1), activator protein 2 (AP-2), and early growth response 1 (Egr-1).[2] This gene is a mitochondrial member of the iron/manganese superoxide dismutase family.[1][3] It encodes a mitochondrial matrix protein that forms a homotetramer and binds one manganese ion per subunit.[1][2] The manganese site forms a trigonal bipyramidal geometry with four ligands from the protein and a fifth solvent ligand. This solvent ligand is a hydroxide believed to serve as the electron acceptor of the enzyme. The active site cavity consists of a network of side chains of several residues associated by hydrogen bonding, extending from the aqueous ligand of the metal. Of note, the highly conserved residue Tyr34 plays a key role in the hydrogen-bonding network, as nitration of this residue inhibits the protein's catalytic ability.[4] This protein also possesses an N-terminal mitochondrial leader sequence which targets it to the mitochondrial matrix, where it converts mitochondrial-generated reactive oxygen species from the respiratory chain to H2.[2] Alternate transcriptional splice variants, encoding different isoforms, have been characterized.[1] # Function As a member of the iron/manganese superoxide dismutase family, this protein transforms toxic superoxide, a byproduct of the mitochondrial electron transport chain, into hydrogen peroxide and diatomic oxygen.[1] This function allows SOD2 to clear mitochondrial reactive oxygen species (ROS) and, as a result, confer protection against cell death.[3] As a result, this protein plays an antiapoptotic role against oxidative stress, ionizing radiation, and inflammatory cytokines.[2] # Clinical significance The SOD2 enzyme is an important constituent in apoptotic signaling and oxidative stress, most notably as part of the mitochondrial death pathway and cardiac myocyte apoptosis signaling.[5] Programmed cell death is a distinct genetic and biochemical pathway essential to metazoans. An intact death pathway is required for successful embryonic development and the maintenance of normal tissue homeostasis. Apoptosis has proven to be tightly interwoven with other essential cell pathways. The identification of critical control points in the cell death pathway has yielded fundamental insights for basic biology, as well as provided rational targets for new therapeutics a normal embryologic processes, or during cell injury (such as ischemia-reperfusion injury during heart attacks and strokes) or during developments and processes in cancer, an apoptotic cell undergoes structural changes including cell shrinkage, plasma membrane blebbing, nuclear condensation, and fragmentation of the DNA and nucleus. This is followed by fragmentation into apoptotic bodies that are quickly removed by phagocytes, thereby preventing an inflammatory response.[6] It is a mode of cell death defined by characteristic morphological, biochemical and molecular changes. It was first described as a "shrinkage necrosis", and then this term was replaced by apoptosis to emphasize its role opposite mitosis in tissue kinetics. In later stages of apoptosis the entire cell becomes fragmented, forming a number of plasma membrane-bounded apoptotic bodies which contain nuclear and or cytoplasmic elements. The ultrastructural appearance of necrosis is quite different, the main features being mitochondrial swelling, plasma membrane breakdown and cellular disintegration. Apoptosis occurs in many physiological and pathological processes. It plays an important role during embryonal development as programmed cell death and accompanies a variety of normal involutional processes in which it serves as a mechanism to remove "unwanted" cells. ## Role in oxidative stress Most notably, SOD2 is pivotal in reactive oxygen species (ROS) release during oxidative stress by ischemia-reperfusion injury, specifically in the myocardium as part of a heart attack (also known as ischemic heart disease). Ischemic heart disease, which results from an occlusion of one of the major coronary arteries, is currently still the leading cause of morbidity and mortality in western society.[7][8] During ischemia reperfusion, ROS release substantially contribute to the cell damage and death via a direct effect on the cell as well as via apoptotic signals. SOD2 is known to have a capacity to limit the detrimental effects of ROS. As such, SOD2 is important for its cardioprotective effects.[9] In addition, SOD2 has been implicated in cardioprotection against ischemia-reperfusion injury, such as during ischemic preconditioning of the heart.[10] Although a large burst of ROS is known to lead to cell damage, a moderate release of ROS from the mitochondria, which occurs during nonlethal short episodes of ischemia, can play a significant triggering role in the signal transduction pathways of ischemic preconditioning leading to reduction of cell damage. It has even observed that during this release of ROS, SOD2 plays an important role hereby regulating apoptotic signaling and cell death. Due to its cytoprotective effects, overexpression of SOD2 has been linked to increased invasiveness of tumor metastasis.[3] Its role in controlling ROS levels also involves it in ageing, cancer, and neurodegenerative disease.[4] Mutations in this gene have been associated with idiopathic cardiomyopathy (IDC), sporadic motor neuron disease, and cancer. A common polymorphism associated with greater susceptibility to various pathologies is found in the mitochondrial leader targeting sequence (Val9Ala).[11] Mice lacking Sod2 die shortly after birth, indicating that unchecked levels of superoxide are incompatible with mammalian life.[12] However, mice 50% deficient in Sod2 have a normal lifespan and minimal phenotypic defects but do suffer increased DNA damage and increased incidence of cancer.[13] In Drosophila melanogaster, over-expression of Sod2 has been show to increase lifespan by 20%.[14] # Role in Invertebrates SOD2's significant role in oxidative stress management makes it an essential component of the mitochondria. As a result, SOD2 similarly to SOD1 and SOD3 is highly conserved in vertebrates as well as invertebrates (organisms that do not possess a vertebral column). In the study Multiple measures of functionality exhibit progressive decline in a parallel, stochastic fashion in Drosophilla Sod2 mutants.[15] In SOD2 mutants there was a cascade of deterioration within the organ systems. These deterioration were not linear in that one organs system would fail then the other, rather on the contrary the deterioration were parallel, meaning that various systems would be affected at any given time. The build up of ROS's in the flies did play a substantial role in affecting the organ system s of the flies in such a way, that though not all observed flies suffered permanent damage, the damages that were observed were like those associated with old age in mature fruit flies.[13] The tissues that are affected in light of defective SOD2 in invertebrates are the muscles, heart, brain and behavior. ROS's effect on these tissue results in not only loss of cellular function in most cases, but a substantial loss in longevity.[14] Though SOD2's role in oxidative stress management is one that has been accepted for both vertebrates and invertebrates, it's necessity has been question by a study that was conducted on Caenorhabditis elegans (C. elegans). The correlation between the lack of/ defective SOD2 and loss of longevity and function is generally understood, however it was discovered that the removal of some of the five members of the SOD family including SOD2 resulted in the increase in longevity in mutant C. elegans compared to the wild type.[16] # Animal studies When animals are exercised at a relatively high work rate, exercise training promotes an increase in myocardial MnSOD activity. Increased MnSOD activity is required to achieve optimal training-induced protection against both ischemia/reperfusion(IR)-induced cardiac arrhythmias and infarction Using an antisense oligonucleotide against MnSOD to prevent ExTr-induced increases in myocardial MnSOD activity, it was demonstrated that an increase in myocardial MnSOD activity is required to provide training-induced protection against IR-induced myocardial infarction.[17] Using a MnSOD gene silencing approach, reported that prevention of the ExTr-induced increase in myocardial MnSOD resulted in a loss of training-induced protection against IR-mediated arrhythmias.[18] # Interactions The SOD2 gene has been shown to bind: - Sp1,[2] - NF-κB,[2] - AP-1,[2] - AP-2,[2] - Egr-1,[2] - CREB,[2] - p53,[2] and - NFE2L2.[2] The SOD2 protein has been shown to interact with HIV-1 Tat and HIV-1 Vif.[19]

https://www.wikidoc.org/index.php/SOD2

5118eae19de678738dc491238534545706a800ab

wikidoc

SOS1

SOS1 Son of sevenless homolog 1 is a protein that in humans is encoded by the SOS1 gene. # Function RAS genes (e.g., MIM 190020) encode membrane-bound guanine nucleotide-binding proteins that function in the transduction of signals that control cell growth and differentiation. Binding of GTP activates RAS proteins, and subsequent hydrolysis of the bound GTP to GDP and phosphate inactivates signaling by these proteins. GTP binding can be catalyzed by guanine nucleotide exchange factors for RAS, and GTP hydrolysis can be accelerated by GTPase-activating proteins (GAPs). The first exchange factor to be identified for RAS was the S. cerevisiae CDC25 gene product. Genetic analysis indicated that CDC25 is essential for activation of RAS proteins. In Drosophila, the protein encoded by the 'son of sevenless' gene (Sos) contains a domain that shows sequence similarity with the catalytic domain of CDC25. Sos may act as a positive regulator of RAS by promoting guanine nucleotide exchange. # Clinical significance Recent studies also show that mutations in Sos1 can cause Noonan syndrome and hereditary gingival fibromatosis type 1. Noonan syndrome has also been shown to be caused by mutations in KRAS and PTPN11 genes. activators of the MAP kinase pathway. # Interactions SOS1 has been shown to interact with: - ABI1, - BCR gene, - CRK, - EPS8, - Epidermal growth factor receptor, - FRS2, - Grb2, - HRAS, - ITSN1, - MUC1, - NCK1, - PLCG1, - PTPN11, - SH3KBP1, and - SHC1. and

SOS1 Son of sevenless homolog 1 is a protein that in humans is encoded by the SOS1 gene.[1][2] # Function RAS genes (e.g., MIM 190020) encode membrane-bound guanine nucleotide-binding proteins that function in the transduction of signals that control cell growth and differentiation. Binding of GTP activates RAS proteins, and subsequent hydrolysis of the bound GTP to GDP and phosphate inactivates signaling by these proteins. GTP binding can be catalyzed by guanine nucleotide exchange factors for RAS, and GTP hydrolysis can be accelerated by GTPase-activating proteins (GAPs). The first exchange factor to be identified for RAS was the S. cerevisiae CDC25 gene product. Genetic analysis indicated that CDC25 is essential for activation of RAS proteins. In Drosophila, the protein encoded by the 'son of sevenless' gene (Sos) contains a domain that shows sequence similarity with the catalytic domain of CDC25. Sos may act as a positive regulator of RAS by promoting guanine nucleotide exchange.[supplied by OMIM][3] # Clinical significance Recent studies also show that mutations in Sos1 can cause Noonan syndrome[4] and hereditary gingival fibromatosis type 1.[5] Noonan syndrome has also been shown to be caused by mutations in KRAS and PTPN11 genes.[6] activators of the MAP kinase pathway. # Interactions SOS1 has been shown to interact with: - ABI1,[7] - BCR gene,[8][9] - CRK,[10] - EPS8,[7][11] - Epidermal growth factor receptor,[12][13][14] - FRS2,[15][16][17] - Grb2,[8][10][12][15][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] - HRAS,[35][36] - ITSN1,[28] - MUC1,[19][37] - NCK1,[10][38][39][40] - PLCG1,[41][42] - PTPN11,[18][43] - SH3KBP1,[44] and - SHC1.[13][16][18][31] and

https://www.wikidoc.org/index.php/SOS1

f16764fbc60f7e5ccdb78beb8b67d9ab6a47b183

wikidoc

SOX2

SOX2 SRY (sex determining region Y)-box 2, also known as SOX2, is a transcription factor that is essential for maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells. Sox2 has a critical role in maintenance of embryonic and neural stem cells. Sox2 is a member of the Sox family of transcription factors, which have been shown to play key roles in many stages of mammalian development. This protein family shares highly conserved DNA binding domains known as HMG (High-mobility group) box domains containing approximately 80 amino acids. Sox2 holds great promise in research involving induced pluripotency, an emerging and very promising field of regenerative medicine. # Function ## Stem cell pluripotency LIF (Leukemia inhibitory factor) signaling, which maintains pluripotency in mouse embryonic stem cells, activates Sox2 downstream of the JAK-STAT signaling pathway and subsequent activation of Klf4 (a member of the family of Kruppel-like factors). Oct-4, Sox2 and Nanog positively regulate transcription of all pluripotency circuitry proteins in the LIF pathway. NPM1, a transcriptional regulator involved in cell proliferation, individually forms complexes with Sox2, Oct4 and Nanog in embryonic stem cells. These three pluripotency factors contribute to a complex molecular network that regulates a number of genes controlling pluripotency. Sox2 binds to DNA cooperatively with Oct4 at non-palindromic sequences to activate transcription of key pluripotency factors. Surprisingly, regulation of Oct4-Sox2 enhancers can occur without Sox2, likely due to expression of other Sox proteins. However, a group of researchers concluded that the primary role of Sox2 in embryonic stem cells is controlling Oct4 expression, and they both perpetuate their own expression when expressed concurrently. In an experiment involving mouse embryonic stem cells, it was discovered that Sox2 in conjunction with Oct4, c-Myc and Klf4 were sufficient for producing induced pluripotent stem cells. The discovery that expression of only four transcription factors was necessary to induce pluripotency allowed future regenerative medicine research to be conducted considering minor manipulations. Loss of pluripotency is regulated by hypermethylation of some Sox2 and Oct4 binding sites in male germ cells and post-transcriptional suppression of Sox2 by miR134. Varying levels of Sox2 affect embryonic stem cells' fate of differentiation. Sox2 inhibits differentiation into the mesendoderm germ layer and promotes differentiation into neural ectoderm germ layer. Npm1/Sox2 complexes are sustained when differentiation is induced along the ectodermal lineage, emphasizing an important functional role for Sox2 in ectodermal differentiation. A study conducted in Milano, Italy showed, through the development of a knockout model, that deficiency of Sox2 results in neural malformities and eventually fetal death, further underlining Sox2’s vital role in embryonic development. ## Neural stem cells In neurogenesis, Sox2 is expressed throughout developing cells in the neural tube as well as in proliferating central nervous system progenitors. However, Sox2 is downregulated during progenitors' final cell cycle during differentiation when they become post mitotic. Cells expressing Sox2 are capable of both producing cells identical to themselves and differentiated neural cell types, two necessary hallmarks of stem cells. Proliferation of Sox2+ neural stem cells can generate neural precursors as well as Sox2+ neural stem cell population. Induced pluripotency is possible using adult neural stem cells, which express higher levels of Sox2 and c-Myc than embryonic stem cells. Therefore, only two exogenous factors, one of which is necessarily Oct4, are sufficient for inducing pluripotent cells from neural stem cells, lessening the complications and risks associated with introducing multiple factors to induce pluripotency. ## Eye deformities Mutations in this gene have been linked with bilateral anophthalmia, a severe structural eye deformity. ## Cancer In lung development, Sox2 controls the branching morphogenesis of the bronchial tree and differentiation of the epithelium of airways. Overexpression causes an increase in neuroendocrine, gastric/intestinal and basal cells. Under normal conditions, Sox2 is critical for maintaining self-renewal and appropriate proportion of basal cells in adult tracheal epithelium. However, its overexpression gives rise to extensive epithelial hyperplasia and eventually carcinoma in both developing and adult mouse lungs. In squamous cell carcinoma, gene amplifications frequently target the 3q26.3 region. The gene for Sox2 lies within this region, which effectively characterizes Sox2 as an oncogene. Sox2 is a key upregulated factor in lung squamous cell carcinoma, directing many genes involved in tumor progression. Sox2 overexpression cooperates with loss of Lkb1 expression to promote squamous cell lung cancer in mice. Its overexpression also activates cellular migration and anchorage-independent growth. Sox2 expression is also found in high gleason grade prostate cancer, and promotes castration-resistant prostate cancer growth. The ectopic expression of SOX2 may be related to abnormal differentiation of colorectal cancer cells. Sox2 has been shown to be relevant in the development of Tamoxifen resistance in breast cancer. # Regulation by thyroid hormone There are three thyroid hormone response elements (TREs) in the region upstream of the Sox2 promoter. This region is known as the enhancer region. Studies have suggested that thyroid hormone (T3) controls Sox2 expression via the enhancer region. The expression of TRα1 (thyroid hormone receptor) is increased in proliferating and migrating neural stem cells. It has therefore been suggested that transcriptional repression of Sox2, mediated by the thyroid hormone signaling axis, allows for neural stem cell commitment and migration from the sub-ventricular zone. A deficiency of thyroid hormone, particularly during the first trimester, will lead to abnormal central nervous system development. Further supporting this conclusion is the fact that hypothyroidism during fetal development can result in a variety of neurological deficiencies, including cretinism, characterized by stunted physical development and mental retardation. Hypothyroidism can arise from a multitude of causes, and is commonly remedied with hormone treatments such as the commonly used Levothyroxine. # Interactions SOX2 has been shown to interact with PAX6, NPM1, and Oct4. SOX2 has been found to cooperatively regulate Rex1 with Oct3/4.

SOX2 SRY (sex determining region Y)-box 2, also known as SOX2, is a transcription factor that is essential for maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells. Sox2 has a critical role in maintenance of embryonic and neural stem cells.[1] Sox2 is a member of the Sox family of transcription factors, which have been shown to play key roles in many stages of mammalian development. This protein family shares highly conserved DNA binding domains known as HMG (High-mobility group) box domains containing approximately 80 amino acids.[1] Sox2 holds great promise in research involving induced pluripotency, an emerging and very promising field of regenerative medicine.[2] # Function ## Stem cell pluripotency LIF (Leukemia inhibitory factor) signaling, which maintains pluripotency in mouse embryonic stem cells, activates Sox2 downstream of the JAK-STAT signaling pathway and subsequent activation of Klf4 (a member of the family of Kruppel-like factors). Oct-4, Sox2 and Nanog positively regulate transcription of all pluripotency circuitry proteins in the LIF pathway.[3] NPM1, a transcriptional regulator involved in cell proliferation, individually forms complexes with Sox2, Oct4 and Nanog in embryonic stem cells.[4] These three pluripotency factors contribute to a complex molecular network that regulates a number of genes controlling pluripotency. Sox2 binds to DNA cooperatively with Oct4 at non-palindromic sequences to activate transcription of key pluripotency factors.[5] Surprisingly, regulation of Oct4-Sox2 enhancers can occur without Sox2, likely due to expression of other Sox proteins. However, a group of researchers concluded that the primary role of Sox2 in embryonic stem cells is controlling Oct4 expression, and they both perpetuate their own expression when expressed concurrently.[6] In an experiment involving mouse embryonic stem cells, it was discovered that Sox2 in conjunction with Oct4, c-Myc and Klf4 were sufficient for producing induced pluripotent stem cells.[7] The discovery that expression of only four transcription factors was necessary to induce pluripotency allowed future regenerative medicine research to be conducted considering minor manipulations. Loss of pluripotency is regulated by hypermethylation of some Sox2 and Oct4 binding sites in male germ cells[8] and post-transcriptional suppression of Sox2 by miR134.[9] Varying levels of Sox2 affect embryonic stem cells' fate of differentiation. Sox2 inhibits differentiation into the mesendoderm germ layer and promotes differentiation into neural ectoderm germ layer.[10] Npm1/Sox2 complexes are sustained when differentiation is induced along the ectodermal lineage, emphasizing an important functional role for Sox2 in ectodermal differentiation.[4] A study conducted in Milano, Italy showed, through the development of a knockout model, that deficiency of Sox2 results in neural malformities and eventually fetal death, further underlining Sox2’s vital role in embryonic development.[11] ## Neural stem cells In neurogenesis, Sox2 is expressed throughout developing cells in the neural tube as well as in proliferating central nervous system progenitors. However, Sox2 is downregulated during progenitors' final cell cycle during differentiation when they become post mitotic.[12] Cells expressing Sox2 are capable of both producing cells identical to themselves and differentiated neural cell types, two necessary hallmarks of stem cells. Proliferation of Sox2+ neural stem cells can generate neural precursors as well as Sox2+ neural stem cell population.[13] Induced pluripotency is possible using adult neural stem cells, which express higher levels of Sox2 and c-Myc than embryonic stem cells. Therefore, only two exogenous factors, one of which is necessarily Oct4, are sufficient for inducing pluripotent cells from neural stem cells, lessening the complications and risks associated with introducing multiple factors to induce pluripotency.[14] ## Eye deformities Mutations in this gene have been linked with bilateral anophthalmia, a severe structural eye deformity.[15] ## Cancer In lung development, Sox2 controls the branching morphogenesis of the bronchial tree and differentiation of the epithelium of airways. Overexpression causes an increase in neuroendocrine, gastric/intestinal and basal cells.[16] Under normal conditions, Sox2 is critical for maintaining self-renewal and appropriate proportion of basal cells in adult tracheal epithelium. However, its overexpression gives rise to extensive epithelial hyperplasia and eventually carcinoma in both developing and adult mouse lungs.[17] In squamous cell carcinoma, gene amplifications frequently target the 3q26.3 region. The gene for Sox2 lies within this region, which effectively characterizes Sox2 as an oncogene. Sox2 is a key upregulated factor in lung squamous cell carcinoma, directing many genes involved in tumor progression. Sox2 overexpression cooperates with loss of Lkb1 expression to promote squamous cell lung cancer in mice.[18] Its overexpression also activates cellular migration and anchorage-independent growth.[19] Sox2 expression is also found in high gleason grade prostate cancer, and promotes castration-resistant prostate cancer growth.[20] The ectopic expression of SOX2 may be related to abnormal differentiation of colorectal cancer cells.[21] Sox2 has been shown to be relevant in the development of Tamoxifen resistance in breast cancer.[22] # Regulation by thyroid hormone There are three thyroid hormone response elements (TREs) in the region upstream of the Sox2 promoter. This region is known as the enhancer region. Studies have suggested that thyroid hormone (T3) controls Sox2 expression via the enhancer region. The expression of TRα1 (thyroid hormone receptor) is increased in proliferating and migrating neural stem cells. It has therefore been suggested that transcriptional repression of Sox2, mediated by the thyroid hormone signaling axis, allows for neural stem cell commitment and migration from the sub-ventricular zone. A deficiency of thyroid hormone, particularly during the first trimester, will lead to abnormal central nervous system development.[23] Further supporting this conclusion is the fact that hypothyroidism during fetal development can result in a variety of neurological deficiencies, including cretinism, characterized by stunted physical development and mental retardation.[23] Hypothyroidism can arise from a multitude of causes, and is commonly remedied with hormone treatments such as the commonly used Levothyroxine.[24] # Interactions SOX2 has been shown to interact with PAX6,[25] NPM1,[3] and Oct4.[5] SOX2 has been found to cooperatively regulate Rex1 with Oct3/4.[26]

https://www.wikidoc.org/index.php/SOX2

333fc3f29c0ecd019d3149d0d8daee9ba64d14a3

wikidoc

SOX4

SOX4 Transcription factor SOX-4 is a protein that in humans is encoded by the SOX4 gene. # Function This intronless gene encodes a member of the SOX (SRY-related HMG-box) family of transcription factors involved in the regulation of embryonic development and in the determination of the cell fate. The encoded protein may act as a transcriptional regulator after forming a protein complex with other proteins, such as syndecan binding protein (syntenin). The protein may function in the apoptosis pathway leading to cell death as well as to tumorigenesis and may mediate downstream effects of parathyroid hormone (PTH) and PTH-related protein (PTHrP) in bone development. The solution structure has been resolved for the HMG-box of a similar mouse protein. Sox4 is expressed in lymphocytes (B and T) and is required for B lymphocyte development. # Clinical significance A genomic region close to the SOX4 gene has been associated with endometrial cancer development. # Interactions SOX4 has been shown to interact with SDCBP.

SOX4 Transcription factor SOX-4 is a protein that in humans is encoded by the SOX4 gene.[1][2][3] # Function This intronless gene encodes a member of the SOX (SRY-related HMG-box) family of transcription factors involved in the regulation of embryonic development and in the determination of the cell fate. The encoded protein may act as a transcriptional regulator after forming a protein complex with other proteins, such as syndecan binding protein (syntenin). The protein may function in the apoptosis pathway leading to cell death as well as to tumorigenesis and may mediate downstream effects of parathyroid hormone (PTH) and PTH-related protein (PTHrP) in bone development. The solution structure has been resolved for the HMG-box of a similar mouse protein.[3] Sox4 is expressed in lymphocytes (B and T) and is required for B lymphocyte development.[4] # Clinical significance A genomic region close to the SOX4 gene has been associated with endometrial cancer development.[5][6] # Interactions SOX4 has been shown to interact with SDCBP.[7]

https://www.wikidoc.org/index.php/SOX4

eaf772c82ffeaf037a05300c8c851c0b3b486634

wikidoc

SOX6

SOX6 Transcription factor SOX-6 is a protein that in humans is encoded by the SOX6 gene. # Function The SOX gene family encodes a group of transcription factors defined by the conserved high mobility group (HMG) DNA-binding domain. Unlike most transcription factors, SOX transcription factors bind to the minor groove of DNA, causing a 70- to 85-degree bend and introducing local conformational changes. # Interactions SOX6 has been shown to interact with CTBP2 and CENPK. It has also been demonstrated that SOX6 protein accumulates in the differentiating human erythrocytes, and then is able to downregulate its own transcription, by directly binding to an evolutionarily conserved consensus sequences located near SOX6 transcriptional start site. Sox6 appears to have a crucial role in the transcriptional regulation of globin genes, and in directing the terminal differentiation of red blood cells.

SOX6 Transcription factor SOX-6 is a protein that in humans is encoded by the SOX6 gene.[1][2] # Function The SOX gene family encodes a group of transcription factors defined by the conserved high mobility group (HMG) DNA-binding domain. Unlike most transcription factors, SOX transcription factors bind to the minor groove of DNA, causing a 70- to 85-degree bend and introducing local conformational changes.[supplied by OMIM][2] # Interactions SOX6 has been shown to interact with CTBP2[3] and CENPK.[4] It has also been demonstrated that SOX6 protein accumulates in the differentiating human erythrocytes, and then is able to downregulate its own transcription, by directly binding to an evolutionarily conserved consensus sequences located near SOX6 transcriptional start site.[5] Sox6 appears to have a crucial role in the transcriptional regulation of globin genes, and in directing the terminal differentiation of red blood cells.[6]

https://www.wikidoc.org/index.php/SOX6

a9869837191b5c45e124d60b2ec6e2bb99c18c47

wikidoc

SOX9

SOX9 Transcription factor SOX-9 is a protein that in humans is encoded by the SOX9 gene. # Function SOX-9 recognizes the sequence CCTTGAG along with other members of the HMG-box class DNA-binding proteins. It acts during chondrocyte differentiation and, with steroidogenic factor 1, regulates transcription of the anti-Müllerian hormone (AMH) gene. SOX-9 also plays a pivotal role in male sexual development; by working with Sf1, SOX-9 can produce AMH in Sertoli cells to inhibit the creation of a female reproductive system. It also interacts with a few other genes to promote the development of male sexual organs. The process starts when the transcription factor Testis determining factor (encoded by the sex-determining region SRY of the Y chromosome) activates SOX-9 activity by binding to an enhancer sequence upstream of the gene. Next, Sox9 activates FGF9 and forms feedforward loops with FGF9 and PGD2. These loops are important for producing SOX-9; without these loops, SOX-9 would run out and the development of a female would almost certainly ensue. Activation of FGF9 by SOX-9 starts vital processes in male development, such as the creation of testis cords and the multiplication of Sertoli cells. The association of SOX-9 and Dax1 actually creates Sertoli cells, another vital process in male development. # Clinical significance Mutations lead to the skeletal malformation syndrome campomelic dysplasia, frequently with autosomal sex-reversal and cleft palate. SOX9 sits in a gene desert on 17q24 in humans. Deletions, disruptions by translocation breakpoints and a single point mutation of highly conserved non-coding elements located > 1 Mb from the transcription unit on either side of SOX9 have been associated with Pierre Robin Sequence, often with a cleft palate. ## Role in sex reversal Mutations in Sox9 or any associated genes can cause reversal of sex and hermaphroditism (or intersexuality in humans). If Fgf9, which is activated by Sox9, is not present, a fetus with both X and Y chromosomes can develop female gonads; the same is true if Dax1 is not present. The related phenomena of hermaphroditism can be caused by unusual activity of the SRY, usually when it's translocated onto the X-chromosome and its activity is only activated in some cells. # Interactions SOX9 has been shown to interact with Steroidogenic factor 1, MED12 and MAF.

SOX9 Transcription factor SOX-9 is a protein that in humans is encoded by the SOX9 gene.[1][2] # Function SOX-9 recognizes the sequence CCTTGAG along with other members of the HMG-box class DNA-binding proteins. It acts during chondrocyte differentiation and, with steroidogenic factor 1, regulates transcription of the anti-Müllerian hormone (AMH) gene.[2] SOX-9 also plays a pivotal role in male sexual development; by working with Sf1, SOX-9 can produce AMH in Sertoli cells to inhibit the creation of a female reproductive system.[3] It also interacts with a few other genes to promote the development of male sexual organs. The process starts when the transcription factor Testis determining factor (encoded by the sex-determining region SRY of the Y chromosome) activates SOX-9 activity by binding to an enhancer sequence upstream of the gene.[4] Next, Sox9 activates FGF9 and forms feedforward loops with FGF9[5] and PGD2.[4] These loops are important for producing SOX-9; without these loops, SOX-9 would run out and the development of a female would almost certainly ensue. Activation of FGF9 by SOX-9 starts vital processes in male development, such as the creation of testis cords and the multiplication of Sertoli cells.[5] The association of SOX-9 and Dax1 actually creates Sertoli cells, another vital process in male development.[6] # Clinical significance Mutations lead to the skeletal malformation syndrome campomelic dysplasia, frequently with autosomal sex-reversal[2] and cleft palate.[7] SOX9 sits in a gene desert on 17q24 in humans. Deletions, disruptions by translocation breakpoints and a single point mutation of highly conserved non-coding elements located > 1 Mb from the transcription unit on either side of SOX9 have been associated with Pierre Robin Sequence, often with a cleft palate.[7][8] ## Role in sex reversal Mutations in Sox9 or any associated genes can cause reversal of sex and hermaphroditism (or intersexuality in humans). If Fgf9, which is activated by Sox9, is not present, a fetus with both X and Y chromosomes can develop female gonads;[4] the same is true if Dax1 is not present.[6] The related phenomena of hermaphroditism can be caused by unusual activity of the SRY, usually when it's translocated onto the X-chromosome and its activity is only activated in some cells.[9] # Interactions SOX9 has been shown to interact with Steroidogenic factor 1,[3] MED12[10] and MAF.[11]

https://www.wikidoc.org/index.php/SOX9

271bdfdb7d61a10e105ed590f8b92173cc6f5990

wikidoc

SPEN

SPEN Msx2-interacting protein is a protein that in humans is encoded by the SPEN gene. This gene encodes a hormone inducible transcriptional repressor. Repression of transcription by this gene product can occur through interactions with other repressors, by the recruitment of proteins involved in histone deacetylation, or through sequestration of transcriptional activators. The product of this gene contains a carboxy-terminal domain that permits binding to other corepressor proteins. This domain also permits interaction with members of the NuRD complex, a nucleosome remodeling protein complex that contains deacetylase activity. In addition, this repressor contains several RNA recognition motifs that confer binding to a steroid receptor RNA coactivator; this binding can modulate the activity of both liganded and nonliganded steroid receptors. # Interactions SPEN has been shown to interact with HDAC1, SRA1 and Nuclear receptor co-repressor 2.

SPEN Msx2-interacting protein is a protein that in humans is encoded by the SPEN gene.[1][2][3] This gene encodes a hormone inducible transcriptional repressor. Repression of transcription by this gene product can occur through interactions with other repressors, by the recruitment of proteins involved in histone deacetylation, or through sequestration of transcriptional activators. The product of this gene contains a carboxy-terminal domain that permits binding to other corepressor proteins. This domain also permits interaction with members of the NuRD complex, a nucleosome remodeling protein complex that contains deacetylase activity. In addition, this repressor contains several RNA recognition motifs that confer binding to a steroid receptor RNA coactivator; this binding can modulate the activity of both liganded and nonliganded steroid receptors.[3] # Interactions SPEN has been shown to interact with HDAC1,[2] SRA1[2] and Nuclear receptor co-repressor 2.[2]

https://www.wikidoc.org/index.php/SPEN

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wikidoc

SPI1

SPI1 Transcription factor PU.1 is a protein that in humans is encoded by the SPI1 gene. # Function This gene encodes an ETS-domain transcription factor that activates gene expression during myeloid and B-lymphoid cell development. The nuclear protein binds to a purine-rich sequence known as the PU-box found on enhancers of target genes, and regulates their expression in coordination with other transcription factors and cofactors. The protein can also regulate alternative splicing of target genes. Multiple transcript variants encoding different isoforms have been found for this gene. # Structure The ETS domain is the DNA-binding module of PU.1 and other ETS-family transcription factors. # Interactions SPI1 has been shown to interact with: - FUS, - GATA2, - IRF4, and - NONO.

SPI1 Transcription factor PU.1 is a protein that in humans is encoded by the SPI1 gene.[1] # Function This gene encodes an ETS-domain transcription factor that activates gene expression during myeloid and B-lymphoid cell development[citation needed]. The nuclear protein binds to a purine-rich sequence known as the PU-box found on enhancers of target genes, and regulates their expression in coordination with other transcription factors and cofactors. The protein can also regulate alternative splicing of target genes. Multiple transcript variants encoding different isoforms have been found for this gene.[2] # Structure The ETS domain is the DNA-binding module of PU.1 and other ETS-family transcription factors. # Interactions SPI1 has been shown to interact with: - FUS,[3] - GATA2,[4] - IRF4,[5][6] and - NONO.[7]

https://www.wikidoc.org/index.php/SPI1

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wikidoc

SPOP

SPOP Speckle-type POZ protein is a protein that in humans is encoded by the SPOP gene. This gene encodes a protein that may modulate the transcriptional repression activities of death-associated protein 6 (DAXX), which interacts with histone deacetylase, core histones, and other histone-associated proteins. In mouse, the encoded protein binds to the putative leucine zipper domain of macroH2A1.2, a variant H2A histone that is enriched on inactivated X chromosomes. The BTB/POZ domain of this protein has been shown in other proteins to mediate transcriptional repression and to interact with components of histone deacetylase co-repressor complexes. Alternative splicing of this gene results in multiple transcript variants encoding the same protein. # Clinical relevance Mutations in SPOP lead to a type of prostate tumor thought to be involved in about 15% of all prostate cancers.

SPOP Speckle-type POZ protein is a protein that in humans is encoded by the SPOP gene.[1][2][3] This gene encodes a protein that may modulate the transcriptional repression activities of death-associated protein 6 (DAXX), which interacts with histone deacetylase, core histones, and other histone-associated proteins. In mouse, the encoded protein binds to the putative leucine zipper domain of macroH2A1.2, a variant H2A histone that is enriched on inactivated X chromosomes. The BTB/POZ domain of this protein has been shown in other proteins to mediate transcriptional repression and to interact with components of histone deacetylase co-repressor complexes. Alternative splicing of this gene results in multiple transcript variants encoding the same protein.[3] # Clinical relevance Mutations in SPOP lead to a type of prostate tumor thought to be involved in about 15% of all prostate cancers.[4][5]

https://www.wikidoc.org/index.php/SPOP

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wikidoc

SRA1

SRA1 Steroid receptor RNA activator 1 also known as steroid receptor RNA activator protein (SRAP) is a protein that in humans is encoded by the SRA1 gene. The mRNA transcribed from the SRA1 gene is a component of the ribonucleoprotein complex containing NCOA1. This functional RNA also encodes a protein. # Function This gene is involved in transcriptional coactivation by steroid receptor. There is currently data suggesting this gene encodes both a non-coding RNA that functions as part of a ribonucleoprotein complex and a protein coding mRNA. Increased expression of both the transcript and the protein is associated with cancer. # Interactions SRA1 has been shown to interact with: - Estrogen receptor alpha, - DDX17, - Nuclear receptor coactivator 2, and - SPEN. The SRAP has been shown to interact with its SRA RNA counterpart indirectly with the functional sub-structure STR7 of SRA RNA. Originally proposed to be RRM containing, SRAP has been demonstrated to have a helix bundle at its C-terminal end while N-terminal to this domain appears unstructured.

SRA1 Steroid receptor RNA activator 1 also known as steroid receptor RNA activator protein (SRAP) is a protein that in humans is encoded by the SRA1 gene.[1][2] The mRNA transcribed from the SRA1 gene is a component of the ribonucleoprotein complex containing NCOA1. This functional RNA also encodes a protein.[3] # Function This gene is involved in transcriptional coactivation by steroid receptor. There is currently data suggesting this gene encodes both a non-coding RNA that functions as part of a ribonucleoprotein complex and a protein coding mRNA. Increased expression of both the transcript and the protein is associated with cancer.[2] # Interactions SRA1 has been shown to interact with: - Estrogen receptor alpha,[4] - DDX17,[4] - Nuclear receptor coactivator 2,[4] and - SPEN.[5] The SRAP has been shown to interact with its SRA RNA counterpart indirectly with the functional sub-structure STR7 of SRA RNA.[6] Originally proposed to be RRM containing, SRAP has been demonstrated to have a helix bundle at its C-terminal end while N-terminal to this domain appears unstructured.[7]

https://www.wikidoc.org/index.php/SRA1

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wikidoc

SS18

SS18 Protein SSXT is a protein that in humans is encoded by the SS18 gene. # Function SS18 is a member of the human SWI/SNF chromatin remodeling complex. # Clinical significance SS18 is involved in a chromosomal translocation commonly found in synovial sarcoma. # Interactions SS18 has been shown to interact with: - EP300, - MLLT10, - SMARCA2, and - SMARCB1.

SS18 Protein SSXT is a protein that in humans is encoded by the SS18 gene.[1][2][3] # Function SS18 is a member of the human SWI/SNF chromatin remodeling complex.[4][5][6] # Clinical significance SS18 is involved in a chromosomal translocation commonly found in synovial sarcoma.[7] # Interactions SS18 has been shown to interact with: - EP300,[8] - MLLT10,[9] - SMARCA2,[6] and - SMARCB1.[5]

https://www.wikidoc.org/index.php/SS18

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wikidoc

SSX6

SSX6 SSX family member 6, pseudogene is a protein that in humans is encoded by the SSX6 gene. # Function This gene belongs to the family of highly homologous synovial sarcoma X (SSX) breakpoint proteins. These proteins may function as transcriptional repressors. They are also capable of eliciting spontaneously humoral and cellular immune responses in cancer patients, and are potentially useful targets in cancer vaccine-based immunotherapy. SSX1, SSX2, and SSX4 genes have been involved in the t(X;18) translocation characteristically found in all synovial sarcomas. This gene is classified as a pseudogene because a splice donor in the 3' UTR has changed compared to other family members, rendering the transcript a candidate for nonsense-mediated mRNA decay (NMD). .

SSX6 SSX family member 6, pseudogene is a protein that in humans is encoded by the SSX6 gene. [1] # Function This gene belongs to the family of highly homologous synovial sarcoma X (SSX) breakpoint proteins. These proteins may function as transcriptional repressors. They are also capable of eliciting spontaneously humoral and cellular immune responses in cancer patients, and are potentially useful targets in cancer vaccine-based immunotherapy. SSX1, SSX2, and SSX4 genes have been involved in the t(X;18) translocation characteristically found in all synovial sarcomas. This gene is classified as a pseudogene because a splice donor in the 3' UTR has changed compared to other family members, rendering the transcript a candidate for nonsense-mediated mRNA decay (NMD). [provided by RefSeq, Aug 2009].

https://www.wikidoc.org/index.php/SSX6

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wikidoc

ST14

ST14 Suppressor of tumorigenicity 14 protein, also known as matriptase, is a protein that in humans is encoded by the ST14 gene. ST14 orthologs have been identified in most mammals for which complete genome data are available. # Function Matriptase is an epithelial-derived, integral membrane serine protease. This protease forms a complex with the Kunitz-type serine protease inhibitor, HAI-1, and is found to be activated by sphingosine-1-phosphate. This protease has been shown to cleave and activate hepatocyte growth factor/scatter factor, and urokinase plasminogen activator, which suggest the function of this protease as an epithelial membrane activator for other proteases and latent growth factors. Matriptase is a type II transmembrane serine protease expressed in most human epithelia, where it is coexpressed with its cognate transmembrane inhibitor, hepatocyte growth factor activator inhibitor (HAI)-1. Activation of the matriptase zymogen requires sequential N-terminal cleavage, activation site autocleavage, and transient association with HAI-1. Matriptase has an essential physiological role in profilaggrin processing, corneocyte maturation, and lipid matrix formation associated with terminal differentiation of the oral epithelium and the epidermis, and is also critical for hair follicle growth. Matriptase is an 80- to 90-kDa cell surface glycoprotein with a complex modular structure that is common to all matriptases. # Clinical significance The expression of this protease has been associated with breast, colon, prostate, and ovarian tumors, which implicates its role in cancer invasion, and metastasis. Matriptase and HAI expression are frequently dysregulated in human cancer, and matriptase expression that is unopposed by HAI-1 potently promotes carcinogenesis and metastatic dissemination in animal models.

ST14 Suppressor of tumorigenicity 14 protein, also known as matriptase, is a protein that in humans is encoded by the ST14 gene.[1] ST14 orthologs[2] have been identified in most mammals for which complete genome data are available. # Function Matriptase is an epithelial-derived, integral membrane serine protease. This protease forms a complex with the Kunitz-type serine protease inhibitor, HAI-1, and is found to be activated by sphingosine-1-phosphate. This protease has been shown to cleave and activate hepatocyte growth factor/scatter factor, and urokinase plasminogen activator, which suggest the function of this protease as an epithelial membrane activator for other proteases and latent growth factors.[1] Matriptase is a type II transmembrane serine protease expressed in most human epithelia, where it is coexpressed with its cognate transmembrane inhibitor, hepatocyte growth factor activator inhibitor (HAI)-1. Activation of the matriptase zymogen requires sequential N-terminal cleavage, activation site autocleavage, and transient association with HAI-1. Matriptase has an essential physiological role in profilaggrin processing, corneocyte maturation, and lipid matrix formation associated with terminal differentiation of the oral epithelium and the epidermis, and is also critical for hair follicle growth. Matriptase is an 80- to 90-kDa cell surface glycoprotein with a complex modular structure that is common to all matriptases. # Clinical significance The expression of this protease has been associated with breast, colon, prostate, and ovarian tumors, which implicates its role in cancer invasion, and metastasis.[1] Matriptase and HAI expression are frequently dysregulated in human cancer, and matriptase expression that is unopposed by HAI-1 potently promotes carcinogenesis and metastatic dissemination in animal models.

https://www.wikidoc.org/index.php/ST14

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wikidoc

STIL

STIL SCL-interrupting locus protein is a protein that in humans is encoded by the STIL gene. This gene encodes a cytoplasmic protein implicated in regulation of the mitotic spindle checkpoint, a regulatory pathway that monitors chromosome segregation during cell division to ensure the proper distribution of chromosomes to daughter cells. The protein is phosphorylated in mitosis and in response to activation of the spindle checkpoint, and disappears when cells transition to G1 phase. It interacts with a mitotic regulator, and its expression is required to efficiently activate the spindle checkpoint. It is proposed to regulate Cdc2 kinase activity during spindle checkpoint arrest. Chromosomal deletions that fuse this gene and the adjacent locus commonly occur in T cell leukemias, and are thought to arise through illegitimate recombination events. Multiple transcript variants encoding different isoforms have been found for this gene. Homozygous mutations in the STIL gene cause primary microcephaly (small brain) in humans.

STIL SCL-interrupting locus protein is a protein that in humans is encoded by the STIL gene.[1][2] This gene encodes a cytoplasmic protein implicated in regulation of the mitotic spindle checkpoint, a regulatory pathway that monitors chromosome segregation during cell division to ensure the proper distribution of chromosomes to daughter cells. The protein is phosphorylated in mitosis and in response to activation of the spindle checkpoint, and disappears when cells transition to G1 phase. It interacts with a mitotic regulator, and its expression is required to efficiently activate the spindle checkpoint. It is proposed to regulate Cdc2 kinase activity during spindle checkpoint arrest. Chromosomal deletions that fuse this gene and the adjacent locus commonly occur in T cell leukemias, and are thought to arise through illegitimate recombination events. Multiple transcript variants encoding different isoforms have been found for this gene.[2] Homozygous mutations in the STIL gene cause primary microcephaly (small brain) in humans.

https://www.wikidoc.org/index.php/STIL

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wikidoc

STK4

STK4 Serine/threonine-protein kinase 4 is an enzyme that in humans is encoded by the STK4 gene. # Function The protein encoded by this gene is a cytoplasmic kinase that is structurally similar to the yeast Ste20p (sterile 20 protein) kinase, which acts upstream of the stress-induced mitogen-activated protein kinase (MAPK) cascade. The encoded protein can phosphorylate myelin basic protein and undergoes autophosphorylation. A caspase-cleaved fragment of the encoded protein has been shown to be capable of phosphorylating histone H2B. The particular phosphorylation catalyzed by this protein has been correlated with apoptosis, and it's possible that this protein induces the chromatin condensation observed in this process. # Interactions STK4 has been shown to interact with PRKRIR. STK4 has also been shown to prevent, through Yap1 coactivator modulation, haematological tumor cell apoptosis.

STK4 Serine/threonine-protein kinase 4 is an enzyme that in humans is encoded by the STK4 gene.[1][2][3] # Function The protein encoded by this gene is a cytoplasmic kinase that is structurally similar to the yeast Ste20p (sterile 20 protein) kinase, which acts upstream of the stress-induced mitogen-activated protein kinase (MAPK) cascade. The encoded protein can phosphorylate myelin basic protein and undergoes autophosphorylation. A caspase-cleaved fragment of the encoded protein has been shown to be capable of phosphorylating histone H2B. The particular phosphorylation catalyzed by this protein has been correlated with apoptosis, and it's possible that this protein induces the chromatin condensation observed in this process.[4] # Interactions STK4 has been shown to interact with PRKRIR.[5] STK4 has also been shown to prevent, through Yap1 coactivator modulation, haematological tumor cell apoptosis.[6]

https://www.wikidoc.org/index.php/STK4

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wikidoc

STX2

STX2 Syntaxin-2, also known as epimorphin, is a protein that in humans is encoded by the STX2 gene. The product of this gene belongs to the syntaxin/epimorphin family of proteins. The syntaxins are a large protein family implicated in the targeting and fusion of intracellular transport vesicles. The product of this gene regulates epithelial-mesenchymal interactions and epithelial cell morphogenesis and activation. Alternatively spliced transcript variants encoding different isoforms have been identified. When the N terminus is on the cytosolic face it acts as a t-SNARE involved in intracellular vesicle docking and is called Syntaxin-2. When flipped inside out, i.e. N terminus hangs out on the extracellular surface (by some nonclassical secretion pathway) it acts as a versatile morphogen and is called epimorphin. This membrane protein enjoys the double choice of another form of topological alternatives of being targeted to either apical or basolateral surface of an epithelial cell in a regulated way depending on various contexts. When expressed by mesenchymal cells it can instruct epithelial morphogenesis at epithelial mesenchymal interfaces. # Interactions STX2 has been shown to interact with SNAP-25, SNAP23, STXBP1 and Syntaxin binding protein 3.

STX2 Syntaxin-2, also known as epimorphin, is a protein that in humans is encoded by the STX2 gene.[1][2][3] The product of this gene belongs to the syntaxin/epimorphin family of proteins. The syntaxins are a large protein family implicated in the targeting and fusion of intracellular transport vesicles. The product of this gene regulates epithelial-mesenchymal interactions and epithelial cell morphogenesis and activation. Alternatively spliced transcript variants encoding different isoforms have been identified.[3] When the N terminus is on the cytosolic face it acts as a t-SNARE involved in intracellular vesicle docking and is called Syntaxin-2. When flipped inside out, i.e. N terminus hangs out on the extracellular surface (by some nonclassical secretion pathway) it acts as a versatile morphogen and is called epimorphin. This membrane protein enjoys the double choice of another form of topological alternatives of being targeted to either apical or basolateral surface of an epithelial cell in a regulated way depending on various contexts. When expressed by mesenchymal cells it can instruct epithelial morphogenesis at epithelial mesenchymal interfaces. # Interactions STX2 has been shown to interact with SNAP-25,[4][5] SNAP23,[5][6][7][8] STXBP1[4][9] and Syntaxin binding protein 3.[9]

https://www.wikidoc.org/index.php/STX2

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wikidoc

STX7

STX7 Syntaxin-7 is a protein that in humans is encoded by the STX7 gene. In melanocytic cells STX7 gene expression may be regulated by MITF. # Interactions STX7 has been shown to interact with STX8, VPS18, Vesicle-associated membrane protein 8 and VPS11.

STX7 Syntaxin-7 is a protein that in humans is encoded by the STX7 gene.[1][2] In melanocytic cells STX7 gene expression may be regulated by MITF.[3] # Interactions STX7 has been shown to interact with STX8,[4] VPS18,[5] Vesicle-associated membrane protein 8[4][6] and VPS11.[5]

https://www.wikidoc.org/index.php/STX7

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wikidoc

STX8

STX8 Syntaxin-8 is a protein that in humans is encoded by the STX8 gene. Syntaxin 8 directly interacts with HECTd3 and has similar subcellular localization. The protein has been shown to form the SNARE complex with syntaxin 7, vti1b and endobrevin. These function as the machinery for the homotypic fusion of late endosomes. # Model organisms Model organisms have been used in the study of STX8 function. A conditional knockout mouse line, called Stx8tm2a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program—a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists—at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty four tests were carried out on homozygous mutant adult mice, however no significant abnormalities were observed. # Interactions STX8 has been shown to interact with Vesicle-associated membrane protein 8, VTI1B and STX7.

STX8 Syntaxin-8 is a protein that in humans is encoded by the STX8 gene.[1][2][3] Syntaxin 8 directly interacts with HECTd3 and has similar subcellular localization.[4] The protein has been shown to form the SNARE complex with syntaxin 7, vti1b and endobrevin. These function as the machinery for the homotypic fusion of late endosomes.[5] # Model organisms Model organisms have been used in the study of STX8 function. A conditional knockout mouse line, called Stx8tm2a(EUCOMM)Wtsi[10][11] was generated as part of the International Knockout Mouse Consortium program—a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists—at the Wellcome Trust Sanger Institute.[12][13][14] Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[8][15] Twenty four tests were carried out on homozygous mutant adult mice, however no significant abnormalities were observed.[8] # Interactions STX8 has been shown to interact with Vesicle-associated membrane protein 8,[16] VTI1B[17][18] and STX7.[16]

https://www.wikidoc.org/index.php/STX8

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wikidoc

SUFU

SUFU Suppressor of fused homolog is a protein that in humans is encoded by the SUFU gene. # Function SUFU encodes a component of the sonic hedgehog (SHH) / patched (PTCH) signaling pathway. Mutations in genes encoding components of this pathway are deleterious for normal development and are associated with cancer-predisposing syndromes (e.g., holoprosencephaly, HPE3; basal cell nevus syndrome, BCNS; and Greig cephalopolysyndactyly syndrome; GCPS). # Interactions SUFU has been shown to interact with GLI1, GLI3 and PEX26.

SUFU Suppressor of fused homolog is a protein that in humans is encoded by the SUFU gene.[1][2] # Function SUFU encodes a component of the sonic hedgehog (SHH) / patched (PTCH) signaling pathway. Mutations in genes encoding components of this pathway are deleterious for normal development and are associated with cancer-predisposing syndromes (e.g., holoprosencephaly, HPE3; basal cell nevus syndrome, BCNS; and Greig cephalopolysyndactyly syndrome; GCPS).[2] # Interactions SUFU has been shown to interact with GLI1,[3][4][5] GLI3[6] and PEX26.[7]

https://www.wikidoc.org/index.php/SUFU

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wikidoc

SYT1

SYT1 Synaptotagmin-1 is a protein that in humans is encoded by the SYT1 gene. # Function The synaptotagmins are integral membrane proteins of synaptic vesicles thought to serve as sensors for calcium ions (Ca2+)in the process of vesicular trafficking and exocytosis. Calcium ion binding to synaptotagmin I participates in triggering neurotransmitter release at the synapse (Fernandez-Chacon et al., 2001). SYT1 is the master switch responsible for allowing the human brain to release neurotransmitters. SYT1 senses calcium ion concentrations as low as 10 ppm and subsequently signals the SNARE complex to open fusion pores. # Interactions SYT1 has been shown to interact with SNAP-25, STX1A and S100A13.

SYT1 Synaptotagmin-1 is a protein that in humans is encoded by the SYT1 gene.[1] # Function The synaptotagmins are integral membrane proteins of synaptic vesicles thought to serve as sensors for calcium ions (Ca2+)in the process of vesicular trafficking and exocytosis. Calcium ion binding to synaptotagmin I participates in triggering neurotransmitter release at the synapse (Fernandez-Chacon et al., 2001). [Supplied by OMIM][2] SYT1 is the master switch responsible for allowing the human brain to release neurotransmitters. SYT1 senses calcium ion concentrations as low as 10 ppm and subsequently signals the SNARE complex to open fusion pores.[3] # Interactions SYT1 has been shown to interact with SNAP-25,[4][5] STX1A[6][7] and S100A13.[8][9]

https://www.wikidoc.org/index.php/SYT1

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wikidoc

SZT2

SZT2 Seizure threshold 2 homolog is a protein that in humans is encoded by the SZT2 gene. # Function The protein encoded by this gene is expressed in the brain, predominantly in the parietal and frontal cortex as well as in dorsal root ganglia. It is localized to the peroxisome, and is implicated in resistance to oxidative stress. It likely functions by increasing superoxide dismutase (SOD) activity, but itself has no direct SOD activity. Studies in mice show that this gene confers low seizure threshold, and may also enhance epileptogenesis. # Clinical significance Mutations in this gene have been shown to cause infantile encephalopathy with epilepsy and dysmorphic corpus callosum.

SZT2 Seizure threshold 2 homolog is a protein that in humans is encoded by the SZT2 gene.[1] # Function The protein encoded by this gene is expressed in the brain, predominantly in the parietal and frontal cortex as well as in dorsal root ganglia. It is localized to the peroxisome, and is implicated in resistance to oxidative stress. It likely functions by increasing superoxide dismutase (SOD) activity, but itself has no direct SOD activity. Studies in mice show that this gene confers low seizure threshold, and may also enhance epileptogenesis.[1] # Clinical significance Mutations in this gene have been shown to cause infantile encephalopathy with epilepsy and dysmorphic corpus callosum.[2]

https://www.wikidoc.org/index.php/SZT2

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wikidoc

Seed

Seed A seed is a small embryonic plant enclosed in a covering called the seed coat, usually with some stored food. It is the product of the ripened ovule of gymnosperm and angiosperm plants which occurs after fertilization and some growth within the mother plant. The formation of the seed completes the process of reproduction in seed plants (started with the development of flowers and pollination), with the embryo developed from the zygote and the seed coat from the integuments of the ovule. Seeds have been an important development in the reproduction and spread of flowering plants, relative to more primitive plants like mosses, ferns and liverworts, which do not have seeds and use other means to propagate themselves. This can be seen by the success of seed plants (both gymnosperms and angiosperms) in dominating biological niches on land, from forests to grasslands both in hot and cold climates. The term seed also has a general meaning that predates the above — anything that can be sown i.e. "seed" potatoes, "seeds" of corn or sunflower "seeds". In the case of sunflower and corn "seeds", what is sown is the seed enclosed in a shell or hull, and the potato is a tuber. # Seed structure A typical seed includes three basic parts: (1) an embryo, (2) a supply of nutrients for the embryo, and (3) a seed coat. The embryo is an immature plant from which a new plant will grow under proper conditions. The embryo has one cotyledon or seed leaf in monocotyledons, two cotyledons in almost all dicotyledons and two or more in gymnosperms. The radicle is the embryonic root. The plumule is the embryonic shoot. The embryonic stem above the point of attachment of the cotyledon(s) is the epicotyl. The embryonic stem below the point of attachment is the hypocotyl. Within the seed, there usually is a store of nutrients for the seedling that will grow from the embryo. The form of the stored nutrition varies depending on the kind of plant. In angiosperms, the stored food begins as a tissue called the endosperm, which is derived from the parent plant via double fertilization. The usually triploid endosperm is rich in oil or starch and protein. In gymnosperms, such as conifers, the food storage tissue is part of the female gametophyte, a haploid tissue. In some species, the embryo is embedded in the endosperm or female gametophyte, which the seedling will use upon germination. In others, the endosperm is absorbed by the embryo as the latter grows within the developing seed, and the cotyledons of the embryo become filled with this stored food. At maturity, seeds of these species have no endosperm and are termed exalbuminous seeds. Some exalbuminous seeds are bean, pea, oak, walnut, squash, sunflower, and radish. Seeds with an endosperm at maturity are termed albuminous seeds. Most monocots (e.g. grasses and palms) and many dicots (e.g. brazil nut and castor bean) have albuminous seeds. All gymnosperm seeds are albuminous. The seed coat (or testa) develops from the tissue, the integument, originally surrounding the ovule. The seed coat in the mature seed can be a paper-thin layer (e.g. peanut) or something more substantial (e.g. thick and hard in honey locust and coconut). The seed coat helps protect the embryo from mechanical injury and from drying out. In addition to the three basic seed parts, some seeds have an appendage on the seed coat such an aril (as in yew and nutmeg) or an elaiosome (as in Corydalis) or hairs (as in cotton). There may also be a scar on the seed coat, called the hilum; it is where the seed was attached to the ovary wall by the funiculus. # Seed production Seeds are produced in several related groups of plants, and their manner of production distinguishes the angiosperms ("enclosed seeds") from the gymnosperms ("naked seeds"). Angiosperm seeds are produced in a hard or fleshy (or with layers of both) structure called a fruit that encloses the seeds, hence the name. In gymnosperms, no special structure develops to enclose the seeds, which begin their development "naked" on the bracts of cones. However, the seeds do become covered by the cone scales as they develop in some species of conifer. ## Kinds of seeds There are a number of modifications to seeds by different groups of plants. One example is that of the so-called stone fruits (such as the peach), where a hardened fruit layer ( the endocarp) surrounds the actual seed and is fused to it. Many structures commonly referred to as "seeds" are actually dry fruits. Sunflower seeds are sold commercially while still enclosed within the hard wall of the fruit, which must be split open to reach the seed. ## Seed development The seed, which is an embryo with two points of growth (one of which forms the stems the other the roots) is enclosed in a seed coat with some food reserves. Angiosperm seeds consist of three genetically distinct constituents: (1) the embryo formed from the zygote, (2) the endosperm, which is normally triploid, (3) the seed coat from tissue derived from the maternal tissue of the ovule. In angiosperms, the process of seed development begins with double fertilization and involves the fusion of the egg and sperm nuclei into a zygote. The second part of this process is the fusion of the polar nuclei with a second sperm cell nucleus, thus forming a primary endosperm. Right after fertilization the zygote is mostly inactive but the primary endosperm divides rapidly to form the endosperm tissue. This tissue becomes the food that the young plant will consume until the roots have developed after germination or it develops into a hard seed coat. The seed coat forms from the two integuments or outer layers of cells of the ovule, which derive from tissue from the mother plant, the inner integument forms the tegmen and the outer forms the testa. When the seed coat forms from only one layer it is also called the testa, though not all such testa are homologous from one species to the next. In gymnosperms, the two sperm cells transferred from the pollen do not develop seed by double fertilization but instead only one sperm fertilizes the egg while the other is not used. The seed is composed of the embryo (the result of fertilization) and tissue from the mother plant, which also form a cone around the seed in coniferous plants like Pine and Spruce. The ovules after fertilization develop into the seeds; the main parts of the ovule are the funicle; which attaches the ovule to the placenta, the nucellus; the main region of the ovule were the embryo sac develops, the micropyle; A small pore or opening in the ovule where the pollen tube usually enters during the process of fertilization, and the chalaza; the base of the ovule opposite the micropyle, where integument and nucellus are joined together. The shape of the ovules as they develop often affects the finale shape of the seeds. Plants generally produce ovules of four shapes: the most common shape is called anatropous, with a curved shape. Orthotropous ovules are straight with all the parts of the ovule lined up in a long row producing an uncurved seed. Campylotropous ovules have a curved embryo sac often giving the seed a tight “c” shape. The last ovule shape is called amphitropous, where the ovule is partly inverted and turned back 90 degrees on its stalk or funicle. In the majority of flowering plants the zygotes first division is transversely orientated in regards to the long axis and this establishes the polarity of the embryo. The upper or chalazal pole becomes the main area of growth of the embryo, while the lower or micropylar pole produces the stalk-like suspensor that attaches to the micropyle. The suspensor absorbs and manufacturers nutrients from the endosperm that are utilized during the embryos growth. The embryo is composed of different parts; the epicotyle will grow into the shoot, the radicle grows into the primary root, the hypocotyl connects the epicotyle and the radicle, the cotyledons form the seed leaves, the testa or seed coat forms the outer covering of the seed. Monocotyledonous plants like corn, have other structures; instead of the hypocotyle-epicotyle, it has a coleoptile that forms the first leaf and connects to the coleorhiza that connects to the primary root and adventitious roots form from the sides. The seeds of corn are constructed with these structures; pericarp, scutellum (single large cotyledon) that absorbs nutrients from the endosperm, endosperm, plumule, radicle, coleoptile and coleorhiza - these last two structures are sheath-like and enclose the plumule and radicle, acting as a protective covering. The testa or seed coats of both monocots and dicots are often marked with patterns and textured markings, or have wings or tufts of hair. ## Seed size and seed set Seeds are very diverse in size. The dust-like orchid seeds are the smallest with about one million seeds per gram. Embryotic seeds have immature embryos and no significant energy reserves. They are myco-heterotrophs, depending on mycorrhizal fungi for nutrition during germination and the early growth of the seedling, in fact some terrestrial Orchid seedlings spend the first few years of their life deriving energy from the fungus and do not produce green leaves. At over 20 kg, the largest seed is the coco de mer. Plants that produce smaller seeds can generate many more seeds while plants with larger seeds invest more resources into those seeds and normally produce fewer seeds. Small seeds are quicker to ripen and can be dispersed sooner, so fall blooming plants often have small seeds. Many annual plants produce great quantities of smaller seeds; this helps to ensure that at least a few will end in a favorable place for growth. Herbaceous perennials and woody plants often have larger seeds, they can produce seeds over many years, and larger seeds have more energy reserves for germination and seedling growth and produce larger, more established seedlings. # Seed functions Seeds serve several functions for the plants that produce them. Key among these functions are nourishment of the embryo, dispersal to a new location, and dormancy during unfavorable conditions. Seeds fundamentally are a means of reproduction and most seeds are the product of sexual reproduction which produces a remixing of genetic material and phenotype variability that natural selection acts on. ## Embryo nourishment Seeds protect and nourish the embryo or baby plant. Seeds usually give a seedling a faster start than a sporling from a spore gets because of the larger food reserves in the seed. ## Seed dispersal Unlike animals, plants are limited in their ability to seek out favorable conditions for life and growth. As a consequence, plants have evolved many ways to disperse their offspring by dispersing their seeds (see also vegetative reproduction). A seed must somehow "arrive" at a location and be there at a time favorable for germination and growth. When the fruits open and release their seeds in a regular way, it is called dehiscent, which is often distinctive for related groups of plants, these fruits include; Capsules, follicles, legumes, silicles and siliques. When fruits do not open and release their seeds in a regular fashion they are called indehiscent, which include these fruits; Achenes, caryopsis, nuts, samaras, and utricles. Seed dispersal is seen most obviously in fruits; however many seeds aid in their own dispersal. Some kinds of seeds are dispersed while still inside a fruit or cone, which later opens or disintegrates to release the seeds. Other seeds are expelled or released from the fruit prior to dispersal. For example, milkweeds produce a fruit type, known as a follicle, that splits open along one side to release the seeds. Iris capsules split into three "valves" to release their seeds. ### By wind (anemochory) - Many seeds (e.g. maple, pine) have a wing that aids in wind dispersal. - The dustlike seeds of orchids are carried efficiently by the wind. - Some seeds, (e.g. dandelion, milkweed, poplar) have hairs that aid in wind dispersal. ### By water (hydrochory) - Some plants, such as Mucuna and Dioclea, produce buoyant seeds termed sea-beans or drift seeds because they float in rivers to the oceans and wash up on beaches. ### By animals (zoochory) - Seeds (burrs) with barbs or hooks (e.g. acaena, burdock, dock which attach to animal fur or feathers, and then drop off later. - Seeds with a fleshy covering (e.g. apple, cherry, juniper) are eaten by animals (birds, mammals) which then disperse these seeds in their droppings. - Seeds (nuts) which are an attractive long-term storable food resource for animals (e.g. acorns, hazelnut, walnut); the seeds are stored some distance from the parent plant, and some escape being eaten if the animal forgets them. Myrmecochory is the dispersal of seeds by ants. Foraging ants disperse seeds which have appendages called elaiosomes (e.g. bloodroot, trilliums, Acacias, and many species of Proteaceae). Elaiosomes are soft, fleshy structures that contain nutrients for animals that eat them. The ants carry such seeds back to their nest, where the elaiosomes are eaten. The remainder of the seed, which is hard and inedible to the ants, then germinates either within the nest or at a removal site where the seed has been discarded by the ants. This dispersal relationship is an example of mutualism, since the plants depend upon the ants to disperse seeds, while the ants depend upon the plants seeds for food. As a result, a drop in numbers of one partner can reduce success of the other. In South Africa, the Argentine ant (Linepithema humile) has invaded and displaced native species of ants. Unlike the native ant species, Argentine ants do not collect the seeds of Mimetes cucullatus or eat the elaiosomes. In areas where these ants have invaded, the numbers of Mimetes seedlings have dropped. ## Seed dormancy and protection One important function of most seeds is delaying germination, which allows time for dispersal and prevents germination of all the seeds at one time when conditions appear favorable. The staggering of germination safeguards some seeds or seedlings from suffering during short periods of bad weather, transient herbivores or competition from other plants for light and nutrients. Many species of plants have seeds that germinate over many months or years, and some seeds can remain in the soil seed bank for more than 50 years before germination. Seed dormancy is defined as a seed failing to germinate under environmental conditions optimal for germination, normally when the seed's environment is at the right temperature with proper soil moisture conditions. Induced dormancy or seed quiescence occurs when a seed fails to germinate because the external environmental conditions are inappropriate for germination, mostly in response to being too cold or hot, or too dry. True dormancy or innate dormancy is caused by conditions within the seed that prevent germination under normally ideal conditions. Often seed dormancy is divided into four major categories: exogenous; endogenous; combinational; and secondary. Exogenous dormancy is caused by conditions outside the embryo including: - Hard seed coats or physical dormancy occurs when seeds are impermeable to water or the exchange of gases. In some seeds the seed coat physically prevents the seedling from growing. - Chemical dormancy includes growth regulators etc. Endogenous dormancy is caused by conditions within the embryo itself, including: - Immature embryos where some plants release their seeds before the tissues of the embryos have fully differentiated, and the seeds ripen after they take in water while on the ground, germination can be delayed from a few weeks to a few months. - Morphological dormancy where seeds have fully differentiated embryos that need to grow more before seed germination, the embryos are not yet fully developed. - Morphophysiological dormancy seeds with underdeveloped embryos, and in addition have physiological components to dormancy. These seeds therefore require a dormancy-breaking treatments as well as a period of time to develop fully grown embryos. - Physiological dormancy prevents seed germination until the chemical inhibitors are broken down or are no longer produced by the seed, often physiological dormancy is broken by a period of cool moist conditions, normally below (+4C) 39F, or in the case of many species in Ranunculaceae and a few others,(-5C) 24F. Other chemicals that prevent germination are washed out of the seeds by rainwater or snow melt. Abscisic acid is usually the growth inhibitor in seeds and its production can be affected by light. Some plants like Peony species have multiple types of physiological dormancy, one affects radical growth while the other affects shoot growth. Drying; some plants including a number of grasses and those from seasonally arid regions need a period of drying before they will germinate, the seeds are released but need to have a lower moister content before germination can begin. If the seeds remain moist after dispersal, germination can be delayed for many months or even years. Many herbaceous plants from temperate climate zones have physiological dormancy that disappears with drying of the seeds. Other species will germinate after dispersal only under very narrow temperature ranges, but as the seeds dry they are able to germinate over a wider temperature range. Photodormancy or light sensitivity affects germination of some seeds. These photoblastic seeds need a period of darkness or light to germinate. In species with thin seed coats, light may be able to penetrate into the dormant embryo. The presence of light or the absence of light may trigger the germination process, inhibiting germination in some seeds buried too deeply or in others not buried in the soil. Thermodormancy is seed sensitivity to heat or cold. Some seeds including cocklebur and amaranth germinate only at high temperatures (30C or 86F) many plants that have seed that germinate in early to mid summer have thermodormancy and germinate only when the soil temperature is warm. Other seeds need cool soils to germinate, while others like celery are inhibited when soil temperatures are too warm. Often thermodormancy requirements disappear as the seed ages or dries. - Drying; some plants including a number of grasses and those from seasonally arid regions need a period of drying before they will germinate, the seeds are released but need to have a lower moister content before germination can begin. If the seeds remain moist after dispersal, germination can be delayed for many months or even years. Many herbaceous plants from temperate climate zones have physiological dormancy that disappears with drying of the seeds. Other species will germinate after dispersal only under very narrow temperature ranges, but as the seeds dry they are able to germinate over a wider temperature range. - Photodormancy or light sensitivity affects germination of some seeds. These photoblastic seeds need a period of darkness or light to germinate. In species with thin seed coats, light may be able to penetrate into the dormant embryo. The presence of light or the absence of light may trigger the germination process, inhibiting germination in some seeds buried too deeply or in others not buried in the soil. - Thermodormancy is seed sensitivity to heat or cold. Some seeds including cocklebur and amaranth germinate only at high temperatures (30C or 86F) many plants that have seed that germinate in early to mid summer have thermodormancy and germinate only when the soil temperature is warm. Other seeds need cool soils to germinate, while others like celery are inhibited when soil temperatures are too warm. Often thermodormancy requirements disappear as the seed ages or dries. Combinational dormancy also called double dormancy. Many seeds have more than one type of dormancy, some Iris species have both hard impermeable seeds coats and physiological dormancy. Secondary dormancy is caused by conditions after the seed has been dispersed and occurs in some seeds when none dormant seed is exposed to conditions that are not favorable to germination, very often high temperatures. The mechanisms of secondary dormancy is not yet fully understood but might involve the lose of sensitivity in receptors in the plasma membrane. Many garden plants have seeds that will germinate readily as soon as they have water and are warm enough, though their wild ancestors may have had dormancy, these cultivated plants lack seed dormancy. After many generations of selective pressure by plant breeders and gardeners dormancy has been selected out. For annuals, seeds are a way for the species to survive dry or cold seasons. Ephemeral plants are usually annuals that can go from seed to seed in as few as six weeks. Not all seeds undergo a period of dormancy. Seeds of some mangroves are viviparous, they begin to germinate while still attached to the parent. The large, heavy root allows the seed to penetrate into the ground when it falls. # Seed germination Seed germination is the process of growth of the embryo into a functional plant. It involves the reactivation of the metabolic pathways that lead to growth and the emergence of the radicle or seed root and plumule or shoot. Three fundamental conditions must exist before germination can occur. (1) The embryo must be alive, called seed viability. (2) Any dormancy requirements that prevent germination must be over come. (3) The proper environmental conditions must exist for germination. Seed viability determines the percentage of possible seed germination and is affected by a number of different conditions. Some plants do not produce seeds that have functional complete embryos or the seed may have no embryo at all, often called empty seeds. Predators and pathogens can damage or kill the seed while it is still in the fruit or after it is dispersed. Environmental conditions like flooding or heat can kill the seed before or during germination. The age of the seed affects its health and germination ability, since the seed has a living embryo, over time cells die and cannot be replaced. Some seeds can live for a long time before germination, while others can only survive for a short period after dispersal before they die. Seed vigor is a measure of the quality of seed, and involves the viability of the seed, the germination percentage, germination rate and the strength of the seedlings produced. The germination percentage is simply the proportion of seeds that germinate from all seeds subject to the right conditions for growth. The germination rate is the length of time it takes for the seeds to germinate. Germination percentages and rates are affected by seed viability, dormancy and environmental effects that impact on the seed and seedling. In agriculture and horticulture quality seeds have high viability, measured by germination percentage plus the rate of germination. This is given as a percent of germination over a certain amount of time, 90% germination in 20 days, for example. 'Dormancy' is covered above; many plants produce seeds with varying degrees of dormancy, and different seeds from the same fruit can have different degrees of dormancy. It's possible to have seeds with no dormancy if they are dispersed right away and do not dry (if the seeds dry they go into physiological dormancy). There is great variation amongst plants and a dormant seed is still a viable seed even though the germination rate might be very low. Environmental conditions effecting seed germination include; water, oxygen, temperature and light. Three distinct phases of seed germination occur: water imbibition; lag phase; and radicle emergence. In order for the seed coat to split, the embryo must imbibe (soak up water), which causes it to swell, splitting the seed coat. However, the nature of the seed coat determines how rapidly water can penetrate and subsequently initiate germination. The rate of imbibition is dependent on the permeability of the seed coat, amount of water in the environment and the area of contact the seed has to the source of water. For some seeds, imbibing to much water to quickly can kill the seed. For some seeds, once water is imbibed the germination process can not be stopped and if the seed dries out again it is fatal. While other species have seeds that can imbibe and lose water a few times with out causing ill effects to the seed or drying can cause secondary dormancy. ## Inducing germination A number of different strategies are used by gardeners and horticulturists to break seed dormancy. Scarification of hard seed coats involving the breaking, scratching or softening by chemicals like acids. Other means of scarification include soaking in hot water or poking holes in the seed with a pin. Sometimes fruits are harvested while the seeds are still immature and the seed coat is not fully developed and sown right away. Under natural conditions the seed coats can be broken by rodents chewing on the seeds, rubbing against rocks or freezing and thawing of surface water, battering on rocks in a stream-bed, or passing through an animal's digestive tract. In the latter case, the seed coat protects the seed from digestion, while perhaps weakening the seed coat such that the embryo is ready to sprout when it gets deposited (along with a bit of fertilizer) far from the parent plant. Microorganisms are often effective in breaking down hard seed coats and are sometimes used by people as a treatment, the seeds are stored in a moist warm sandy medium for several months under non-sterile conditions. Stratification also called moist-chilling is a method to break down physiological dormancy and involves the addition of moisture to the seeds so they imbibe water and then the seeds are subject to a period of moist chilling to after-ripen the embryo. Sowing outside in late summer and fall and allowing to overwinter outside under cool conditions is an effective way to stratify seeds, some seeds respond more favorably to periods of osculating temperatures which are part of the natural environment. Leaching or the soaking in water removes chemical inhibitors in some seeds that prevent germination. Rain and melting snow naturally accomplish this task. For seeds that are going to be planted for gardens, the use of running water is best but frequent changes of water are effective too. Normally 12 to 24 hours of soaking is sufficient, longer soaking especially in stagnant water that is not changed can result in oxygen starvation and seed death. Seeds with hard seed coats can be soaked in hot water to break open the impermeable cell layers that prevent water intake. Other methods used to assist in the germination of seeds that have dormancy include prechilling, predrying, daily alternation of temperature, light exposure, potassium nitrate, the use of plant growth regulators like gibberellins, cytokinins, ethylene, thiourea, sodium hypochlorite plus others. # Origin and evolution The origin of seed plants is a problem that still remains unsolved. However, more and more data tends to place this origin in the middle Devonian. The description in 2004 of the proto-seed Runcaria heinzelinii in the Givetian of Belgium is an indication of that ancient origin of seed-plants. As with modern ferns, most land plants before this time reproduced by sending spoor into the air, that would land and become whole new plants. The first "true" seeds are described from the upper Devonian, which is probably the theater of their true first evolutionary radiation. The seed plants progressively became one of the major elements of nearly all ecosystems. # Economic importance ## Edible seeds Many seeds are edible and the majority of human calories comes from seeds, especially from cereals, legumes and nuts. Seeds also provide most cooking oils, many beverages and spices and some important food additives. In different seeds the seed embryo or the endosperm dominates and provides most of the nutrients. The storage proteins of the embryo and endosperm differ in their amino acid content and physical properties. For example the gluten of wheat, important in providing the elastic property to bread dough is strictly an endosperm protein. Seeds are used to propagate many crops such as cereals, legumes, forest trees, turfgrasses and pasture grasses. Seeds are also eaten by animals, and are fed to livestock. Many seeds are used as birdseed. ## Poison and food safety While some seeds are considered by some as healthy to eat, other seeds may be harmful or poisonous, Plants and seeds often contain chemical compounds to discourage herbivores and seed predators. In some cases, these compounds simply taste bad (such as in mustard), but other compounds are toxic, or breakdown into toxic compounds within the digestive system. Children, being smaller than adults, are more susceptible to poisoning or death by plants and seeds. One should be satisfied with reliable food safety information before choosing to eat any particular seeds. An infamously deadly poison, ricin, comes from seeds of the castor bean. Reported lethal doses are anywhere from two to eight seeds, though only a few deaths have been reported when castor beans have been ingested by animals. In addition, seeds containing amygdalin; apple, apricot, bitter almond, peach, plum, cherry, quince, and others, when consumed in significant amounts, may result in cyanide toxicity. Other seeds than contain poisons include annona, cotton, custard apple, datura, uncooked durian, golden chain, horse-chestnut, larkspur, locoweed, lychee, nectarine, rambutan, rosary pea, sour sop, sugar apple, wisteria, and yew. Another seed poison is strychnine. The seeds of many legumes, including the common bean (Phaseolus vulgaris) contain proteins called lectins which can cause gastric distress if the beans are eaten without cooking. The common bean and many others, including the soybean, also contain trypsin inhibitors which interfere with the action of the digestive enzyme trypsin. Normal cooking processes degrade lectins and trypsin inhibitors to harmless forms. ## Other uses The world's most important clothing fiber grows attached to cotton seed. Other seed fibers are from kapok and milkweed. Many important nonfood oils are extracted from seeds. Linseed oil is used in paints. Oil from jojoba and crambe are similar to whale oil. Seeds are the source of some medicines including castor oil, tea tree oil and the discredited cancer drug, Laetrile. Many seeds have been used as beads in necklaces and rosaries including Job's tears, Chinaberry and rosary pea. However, the latter two are also poisonous. Other seed uses include: - Seeds once used as weights for balances. - Seeds used as toys by children, such as for the game conker. - Resin from Clusia rosea seeds used to caulk boats. - Nematicide from milkweed seeds. - Cottonseed meal used as animal feed and fertilizer. # Trivia - The oldest viable carbon-14-dated seed that has grown into a plant was a Judean date palm seed about 2,000 years old, recovered from excavations at Herod the Great's palace on Masada in Israel. It was germinated in 2005. - The largest seed is produced by the coco de mer, or "double coconut palm", Lodoicea maldivica. The entire fruit may weigh up to 23 kilograms (50 pounds) and usually contains a single seed. - The earliest fossil seeds are around 365 million years old from the Late Devonian of West Virginia. The seeds are preserved immature ovules of the plant Elkinsia polymorpha.

Seed A seed is a small embryonic plant enclosed in a covering called the seed coat, usually with some stored food. It is the product of the ripened ovule of gymnosperm and angiosperm plants which occurs after fertilization and some growth within the mother plant. The formation of the seed completes the process of reproduction in seed plants (started with the development of flowers and pollination), with the embryo developed from the zygote and the seed coat from the integuments of the ovule. Seeds have been an important development in the reproduction and spread of flowering plants, relative to more primitive plants like mosses, ferns and liverworts, which do not have seeds and use other means to propagate themselves. This can be seen by the success of seed plants (both gymnosperms and angiosperms) in dominating biological niches on land, from forests to grasslands both in hot and cold climates. The term seed also has a general meaning that predates the above — anything that can be sown i.e. "seed" potatoes, "seeds" of corn or sunflower "seeds". In the case of sunflower and corn "seeds", what is sown is the seed enclosed in a shell or hull, and the potato is a tuber. # Seed structure A typical seed includes three basic parts: (1) an embryo, (2) a supply of nutrients for the embryo, and (3) a seed coat. The embryo is an immature plant from which a new plant will grow under proper conditions. The embryo has one cotyledon or seed leaf in monocotyledons, two cotyledons in almost all dicotyledons and two or more in gymnosperms. The radicle is the embryonic root. The plumule is the embryonic shoot. The embryonic stem above the point of attachment of the cotyledon(s) is the epicotyl. The embryonic stem below the point of attachment is the hypocotyl. Within the seed, there usually is a store of nutrients for the seedling that will grow from the embryo. The form of the stored nutrition varies depending on the kind of plant. In angiosperms, the stored food begins as a tissue called the endosperm, which is derived from the parent plant via double fertilization. The usually triploid endosperm is rich in oil or starch and protein. In gymnosperms, such as conifers, the food storage tissue is part of the female gametophyte, a haploid tissue. In some species, the embryo is embedded in the endosperm or female gametophyte, which the seedling will use upon germination. In others, the endosperm is absorbed by the embryo as the latter grows within the developing seed, and the cotyledons of the embryo become filled with this stored food. At maturity, seeds of these species have no endosperm and are termed exalbuminous seeds. Some exalbuminous seeds are bean, pea, oak, walnut, squash, sunflower, and radish. Seeds with an endosperm at maturity are termed albuminous seeds. Most monocots (e.g. grasses and palms) and many dicots (e.g. brazil nut and castor bean) have albuminous seeds. All gymnosperm seeds are albuminous. The seed coat (or testa) develops from the tissue, the integument, originally surrounding the ovule. The seed coat in the mature seed can be a paper-thin layer (e.g. peanut) or something more substantial (e.g. thick and hard in honey locust and coconut). The seed coat helps protect the embryo from mechanical injury and from drying out. In addition to the three basic seed parts, some seeds have an appendage on the seed coat such an aril (as in yew and nutmeg) or an elaiosome (as in Corydalis) or hairs (as in cotton). There may also be a scar on the seed coat, called the hilum; it is where the seed was attached to the ovary wall by the funiculus. # Seed production Seeds are produced in several related groups of plants, and their manner of production distinguishes the angiosperms ("enclosed seeds") from the gymnosperms ("naked seeds"). Angiosperm seeds are produced in a hard or fleshy (or with layers of both) structure called a fruit that encloses the seeds, hence the name. In gymnosperms, no special structure develops to enclose the seeds, which begin their development "naked" on the bracts of cones. However, the seeds do become covered by the cone scales as they develop in some species of conifer. ## Kinds of seeds There are a number of modifications to seeds by different groups of plants. One example is that of the so-called stone fruits (such as the peach), where a hardened fruit layer ( the endocarp) surrounds the actual seed and is fused to it. Many structures commonly referred to as "seeds" are actually dry fruits. Sunflower seeds are sold commercially while still enclosed within the hard wall of the fruit, which must be split open to reach the seed. ## Seed development The seed, which is an embryo with two points of growth (one of which forms the stems the other the roots) is enclosed in a seed coat with some food reserves. Angiosperm seeds consist of three genetically distinct constituents: (1) the embryo formed from the zygote, (2) the endosperm, which is normally triploid, (3) the seed coat from tissue derived from the maternal tissue of the ovule. In angiosperms, the process of seed development begins with double fertilization and involves the fusion of the egg and sperm nuclei into a zygote. The second part of this process is the fusion of the polar nuclei with a second sperm cell nucleus, thus forming a primary endosperm. Right after fertilization the zygote is mostly inactive but the primary endosperm divides rapidly to form the endosperm tissue. This tissue becomes the food that the young plant will consume until the roots have developed after germination or it develops into a hard seed coat. The seed coat forms from the two integuments or outer layers of cells of the ovule, which derive from tissue from the mother plant, the inner integument forms the tegmen and the outer forms the testa. When the seed coat forms from only one layer it is also called the testa, though not all such testa are homologous from one species to the next. In gymnosperms, the two sperm cells transferred from the pollen do not develop seed by double fertilization but instead only one sperm fertilizes the egg while the other is not used. The seed is composed of the embryo (the result of fertilization) and tissue from the mother plant, which also form a cone around the seed in coniferous plants like Pine and Spruce. The ovules after fertilization develop into the seeds; the main parts of the ovule are the funicle; which attaches the ovule to the placenta, the nucellus; the main region of the ovule were the embryo sac develops, the micropyle; A small pore or opening in the ovule where the pollen tube usually enters during the process of fertilization, and the chalaza; the base of the ovule opposite the micropyle, where integument and nucellus are joined together.[1] The shape of the ovules as they develop often affects the finale shape of the seeds. Plants generally produce ovules of four shapes: the most common shape is called anatropous, with a curved shape. Orthotropous ovules are straight with all the parts of the ovule lined up in a long row producing an uncurved seed. Campylotropous ovules have a curved embryo sac often giving the seed a tight “c” shape. The last ovule shape is called amphitropous, where the ovule is partly inverted and turned back 90 degrees on its stalk or funicle. In the majority of flowering plants the zygotes first division is transversely orientated in regards to the long axis and this establishes the polarity of the embryo. The upper or chalazal pole becomes the main area of growth of the embryo, while the lower or micropylar pole produces the stalk-like suspensor that attaches to the micropyle. The suspensor absorbs and manufacturers nutrients from the endosperm that are utilized during the embryos growth.[2] The embryo is composed of different parts; the epicotyle will grow into the shoot, the radicle grows into the primary root, the hypocotyl connects the epicotyle and the radicle, the cotyledons form the seed leaves, the testa or seed coat forms the outer covering of the seed. Monocotyledonous plants like corn, have other structures; instead of the hypocotyle-epicotyle, it has a coleoptile that forms the first leaf and connects to the coleorhiza that connects to the primary root and adventitious roots form from the sides. The seeds of corn are constructed with these structures; pericarp, scutellum (single large cotyledon) that absorbs nutrients from the endosperm, endosperm, plumule, radicle, coleoptile and coleorhiza - these last two structures are sheath-like and enclose the plumule and radicle, acting as a protective covering. The testa or seed coats of both monocots and dicots are often marked with patterns and textured markings, or have wings or tufts of hair. ## Seed size and seed set Seeds are very diverse in size. The dust-like orchid seeds are the smallest with about one million seeds per gram. Embryotic seeds have immature embryos and no significant energy reserves. They are myco-heterotrophs, depending on mycorrhizal fungi for nutrition during germination and the early growth of the seedling, in fact some terrestrial Orchid seedlings spend the first few years of their life deriving energy from the fungus and do not produce green leaves.[3] At over 20 kg, the largest seed is the coco de mer. Plants that produce smaller seeds can generate many more seeds while plants with larger seeds invest more resources into those seeds and normally produce fewer seeds. Small seeds are quicker to ripen and can be dispersed sooner, so fall blooming plants often have small seeds. Many annual plants produce great quantities of smaller seeds; this helps to ensure that at least a few will end in a favorable place for growth. Herbaceous perennials and woody plants often have larger seeds, they can produce seeds over many years, and larger seeds have more energy reserves for germination and seedling growth and produce larger, more established seedlings. # Seed functions Seeds serve several functions for the plants that produce them. Key among these functions are nourishment of the embryo, dispersal to a new location, and dormancy during unfavorable conditions. Seeds fundamentally are a means of reproduction and most seeds are the product of sexual reproduction which produces a remixing of genetic material and phenotype variability that natural selection acts on. ## Embryo nourishment Seeds protect and nourish the embryo or baby plant. Seeds usually give a seedling a faster start than a sporling from a spore gets because of the larger food reserves in the seed. ## Seed dispersal Unlike animals, plants are limited in their ability to seek out favorable conditions for life and growth. As a consequence, plants have evolved many ways to disperse their offspring by dispersing their seeds (see also vegetative reproduction). A seed must somehow "arrive" at a location and be there at a time favorable for germination and growth. When the fruits open and release their seeds in a regular way, it is called dehiscent, which is often distinctive for related groups of plants, these fruits include; Capsules, follicles, legumes, silicles and siliques. When fruits do not open and release their seeds in a regular fashion they are called indehiscent, which include these fruits; Achenes, caryopsis, nuts, samaras, and utricles.[4] Seed dispersal is seen most obviously in fruits; however many seeds aid in their own dispersal. Some kinds of seeds are dispersed while still inside a fruit or cone, which later opens or disintegrates to release the seeds. Other seeds are expelled or released from the fruit prior to dispersal. For example, milkweeds produce a fruit type, known as a follicle,[5] that splits open along one side to release the seeds. Iris capsules split into three "valves" to release their seeds.[6] ### By wind (anemochory) - Many seeds (e.g. maple, pine) have a wing that aids in wind dispersal. - The dustlike seeds of orchids are carried efficiently by the wind. - Some seeds, (e.g. dandelion, milkweed, poplar) have hairs that aid in wind dispersal. ### By water (hydrochory) - Some plants, such as Mucuna and Dioclea, produce buoyant seeds termed sea-beans or drift seeds because they float in rivers to the oceans and wash up on beaches.[7] ### By animals (zoochory) - Seeds (burrs) with barbs or hooks (e.g. acaena, burdock, dock which attach to animal fur or feathers, and then drop off later. - Seeds with a fleshy covering (e.g. apple, cherry, juniper) are eaten by animals (birds, mammals) which then disperse these seeds in their droppings. - Seeds (nuts) which are an attractive long-term storable food resource for animals (e.g. acorns, hazelnut, walnut); the seeds are stored some distance from the parent plant, and some escape being eaten if the animal forgets them. Myrmecochory is the dispersal of seeds by ants. Foraging ants disperse seeds which have appendages called elaiosomes[8] (e.g. bloodroot, trilliums, Acacias, and many species of Proteaceae). Elaiosomes are soft, fleshy structures that contain nutrients for animals that eat them. The ants carry such seeds back to their nest, where the elaiosomes are eaten. The remainder of the seed, which is hard and inedible to the ants, then germinates either within the nest or at a removal site where the seed has been discarded by the ants.[9] This dispersal relationship is an example of mutualism, since the plants depend upon the ants to disperse seeds, while the ants depend upon the plants seeds for food. As a result, a drop in numbers of one partner can reduce success of the other. In South Africa, the Argentine ant (Linepithema humile) has invaded and displaced native species of ants. Unlike the native ant species, Argentine ants do not collect the seeds of Mimetes cucullatus or eat the elaiosomes. In areas where these ants have invaded, the numbers of Mimetes seedlings have dropped.[10] ## Seed dormancy and protection One important function of most seeds is delaying germination, which allows time for dispersal and prevents germination of all the seeds at one time when conditions appear favorable. The staggering of germination safeguards some seeds or seedlings from suffering during short periods of bad weather, transient herbivores or competition from other plants for light and nutrients. Many species of plants have seeds that germinate over many months or years, and some seeds can remain in the soil seed bank for more than 50 years before germination. Seed dormancy is defined as a seed failing to germinate under environmental conditions optimal for germination, normally when the seed's environment is at the right temperature with proper soil moisture conditions. Induced dormancy or seed quiescence occurs when a seed fails to germinate because the external environmental conditions are inappropriate for germination, mostly in response to being too cold or hot, or too dry. True dormancy or innate dormancy is caused by conditions within the seed that prevent germination under normally ideal conditions. Often seed dormancy is divided into four major categories: exogenous; endogenous; combinational; and secondary. Exogenous dormancy is caused by conditions outside the embryo including: - Hard seed coats or physical dormancy occurs when seeds are impermeable to water or the exchange of gases. In some seeds the seed coat physically prevents the seedling from growing. - Chemical dormancy includes growth regulators etc. Endogenous dormancy is caused by conditions within the embryo itself, including: - Immature embryos where some plants release their seeds before the tissues of the embryos have fully differentiated, and the seeds ripen after they take in water while on the ground, germination can be delayed from a few weeks to a few months. - Morphological dormancy where seeds have fully differentiated embryos that need to grow more before seed germination, the embryos are not yet fully developed. - Morphophysiological dormancy seeds with underdeveloped embryos, and in addition have physiological components to dormancy. These seeds therefore require a dormancy-breaking treatments as well as a period of time to develop fully grown embryos. - Physiological dormancy prevents seed germination until the chemical inhibitors are broken down or are no longer produced by the seed, often physiological dormancy is broken by a period of cool moist conditions, normally below (+4C) 39F, or in the case of many species in Ranunculaceae and a few others,(-5C) 24F. Other chemicals that prevent germination are washed out of the seeds by rainwater or snow melt. Abscisic acid is usually the growth inhibitor in seeds and its production can be affected by light. Some plants like Peony species have multiple types of physiological dormancy, one affects radical growth while the other affects shoot growth. Drying; some plants including a number of grasses and those from seasonally arid regions need a period of drying before they will germinate, the seeds are released but need to have a lower moister content before germination can begin. If the seeds remain moist after dispersal, germination can be delayed for many months or even years. Many herbaceous plants from temperate climate zones have physiological dormancy that disappears with drying of the seeds. Other species will germinate after dispersal only under very narrow temperature ranges, but as the seeds dry they are able to germinate over a wider temperature range.[11] Photodormancy or light sensitivity affects germination of some seeds. These photoblastic seeds need a period of darkness or light to germinate. In species with thin seed coats, light may be able to penetrate into the dormant embryo. The presence of light or the absence of light may trigger the germination process, inhibiting germination in some seeds buried too deeply or in others not buried in the soil. Thermodormancy is seed sensitivity to heat or cold. Some seeds including cocklebur and amaranth germinate only at high temperatures (30C or 86F) many plants that have seed that germinate in early to mid summer have thermodormancy and germinate only when the soil temperature is warm. Other seeds need cool soils to germinate, while others like celery are inhibited when soil temperatures are too warm. Often thermodormancy requirements disappear as the seed ages or dries. - Drying; some plants including a number of grasses and those from seasonally arid regions need a period of drying before they will germinate, the seeds are released but need to have a lower moister content before germination can begin. If the seeds remain moist after dispersal, germination can be delayed for many months or even years. Many herbaceous plants from temperate climate zones have physiological dormancy that disappears with drying of the seeds. Other species will germinate after dispersal only under very narrow temperature ranges, but as the seeds dry they are able to germinate over a wider temperature range.[11] - Photodormancy or light sensitivity affects germination of some seeds. These photoblastic seeds need a period of darkness or light to germinate. In species with thin seed coats, light may be able to penetrate into the dormant embryo. The presence of light or the absence of light may trigger the germination process, inhibiting germination in some seeds buried too deeply or in others not buried in the soil. - Thermodormancy is seed sensitivity to heat or cold. Some seeds including cocklebur and amaranth germinate only at high temperatures (30C or 86F) many plants that have seed that germinate in early to mid summer have thermodormancy and germinate only when the soil temperature is warm. Other seeds need cool soils to germinate, while others like celery are inhibited when soil temperatures are too warm. Often thermodormancy requirements disappear as the seed ages or dries. Combinational dormancy also called double dormancy. Many seeds have more than one type of dormancy,[12] some Iris species have both hard impermeable seeds coats and physiological dormancy. Secondary dormancy is caused by conditions after the seed has been dispersed and occurs in some seeds when none dormant seed is exposed to conditions that are not favorable to germination, very often high temperatures. The mechanisms of secondary dormancy is not yet fully understood but might involve the lose of sensitivity in receptors in the plasma membrane.[13] Many garden plants have seeds that will germinate readily as soon as they have water and are warm enough, though their wild ancestors may have had dormancy, these cultivated plants lack seed dormancy. After many generations of selective pressure by plant breeders and gardeners dormancy has been selected out. For annuals, seeds are a way for the species to survive dry or cold seasons. Ephemeral plants are usually annuals that can go from seed to seed in as few as six weeks.[14] Not all seeds undergo a period of dormancy. Seeds of some mangroves are viviparous, they begin to germinate while still attached to the parent. The large, heavy root allows the seed to penetrate into the ground when it falls. # Seed germination Seed germination is the process of growth of the embryo into a functional plant. It involves the reactivation of the metabolic pathways that lead to growth and the emergence of the radicle or seed root and plumule or shoot. Three fundamental conditions must exist before germination can occur. (1) The embryo must be alive, called seed viability. (2) Any dormancy requirements that prevent germination must be over come. (3) The proper environmental conditions must exist for germination. Seed viability determines the percentage of possible seed germination and is affected by a number of different conditions. Some plants do not produce seeds that have functional complete embryos or the seed may have no embryo at all, often called empty seeds. Predators and pathogens can damage or kill the seed while it is still in the fruit or after it is dispersed. Environmental conditions like flooding or heat can kill the seed before or during germination. The age of the seed affects its health and germination ability, since the seed has a living embryo, over time cells die and cannot be replaced. Some seeds can live for a long time before germination, while others can only survive for a short period after dispersal before they die. Seed vigor is a measure of the quality of seed, and involves the viability of the seed, the germination percentage, germination rate and the strength of the seedlings produced.[15] The germination percentage is simply the proportion of seeds that germinate from all seeds subject to the right conditions for growth. The germination rate is the length of time it takes for the seeds to germinate. Germination percentages and rates are affected by seed viability, dormancy and environmental effects that impact on the seed and seedling. In agriculture and horticulture quality seeds have high viability, measured by germination percentage plus the rate of germination. This is given as a percent of germination over a certain amount of time, 90% germination in 20 days, for example. 'Dormancy' is covered above; many plants produce seeds with varying degrees of dormancy, and different seeds from the same fruit can have different degrees of dormancy.[16] It's possible to have seeds with no dormancy if they are dispersed right away and do not dry (if the seeds dry they go into physiological dormancy). There is great variation amongst plants and a dormant seed is still a viable seed even though the germination rate might be very low. Environmental conditions effecting seed germination include; water, oxygen, temperature and light. Three distinct phases of seed germination occur: water imbibition; lag phase; and radicle emergence. In order for the seed coat to split, the embryo must imbibe (soak up water), which causes it to swell, splitting the seed coat. However, the nature of the seed coat determines how rapidly water can penetrate and subsequently initiate germination. The rate of imbibition is dependent on the permeability of the seed coat, amount of water in the environment and the area of contact the seed has to the source of water. For some seeds, imbibing to much water to quickly can kill the seed. For some seeds, once water is imbibed the germination process can not be stopped and if the seed dries out again it is fatal. While other species have seeds that can imbibe and lose water a few times with out causing ill effects to the seed or drying can cause secondary dormancy. ## Inducing germination A number of different strategies are used by gardeners and horticulturists to break seed dormancy. Scarification of hard seed coats involving the breaking, scratching or softening by chemicals like acids. Other means of scarification include soaking in hot water or poking holes in the seed with a pin. Sometimes fruits are harvested while the seeds are still immature and the seed coat is not fully developed and sown right away. Under natural conditions the seed coats can be broken by rodents chewing on the seeds, rubbing against rocks or freezing and thawing of surface water, battering on rocks in a stream-bed, or passing through an animal's digestive tract. In the latter case, the seed coat protects the seed from digestion, while perhaps weakening the seed coat such that the embryo is ready to sprout when it gets deposited (along with a bit of fertilizer) far from the parent plant. Microorganisms are often effective in breaking down hard seed coats and are sometimes used by people as a treatment, the seeds are stored in a moist warm sandy medium for several months under non-sterile conditions. Stratification also called moist-chilling is a method to break down physiological dormancy and involves the addition of moisture to the seeds so they imbibe water and then the seeds are subject to a period of moist chilling to after-ripen the embryo. Sowing outside in late summer and fall and allowing to overwinter outside under cool conditions is an effective way to stratify seeds, some seeds respond more favorably to periods of osculating temperatures which are part of the natural environment. Leaching or the soaking in water removes chemical inhibitors in some seeds that prevent germination. Rain and melting snow naturally accomplish this task. For seeds that are going to be planted for gardens, the use of running water is best but frequent changes of water are effective too. Normally 12 to 24 hours of soaking is sufficient, longer soaking especially in stagnant water that is not changed can result in oxygen starvation and seed death. Seeds with hard seed coats can be soaked in hot water to break open the impermeable cell layers that prevent water intake. Other methods used to assist in the germination of seeds that have dormancy include prechilling, predrying, daily alternation of temperature, light exposure, potassium nitrate, the use of plant growth regulators like gibberellins, cytokinins, ethylene, thiourea, sodium hypochlorite plus others.[17] # Origin and evolution The origin of seed plants is a problem that still remains unsolved. However, more and more data tends to place this origin in the middle Devonian. The description in 2004 of the proto-seed Runcaria heinzelinii in the Givetian of Belgium is an indication of that ancient origin of seed-plants. As with modern ferns, most land plants before this time reproduced by sending spoor into the air, that would land and become whole new plants. The first "true" seeds are described from the upper Devonian, which is probably the theater of their true first evolutionary radiation. The seed plants progressively became one of the major elements of nearly all ecosystems. # Economic importance ## Edible seeds Many seeds are edible and the majority of human calories comes from seeds, especially from cereals, legumes and nuts. Seeds also provide most cooking oils, many beverages and spices and some important food additives. In different seeds the seed embryo or the endosperm dominates and provides most of the nutrients. The storage proteins of the embryo and endosperm differ in their amino acid content and physical properties. For example the gluten of wheat, important in providing the elastic property to bread dough is strictly an endosperm protein. Seeds are used to propagate many crops such as cereals, legumes, forest trees, turfgrasses and pasture grasses. Seeds are also eaten by animals, and are fed to livestock. Many seeds are used as birdseed. ## Poison and food safety While some seeds are considered by some as healthy to eat, other seeds may be harmful or poisonous,[18] Plants and seeds often contain chemical compounds to discourage herbivores and seed predators. In some cases, these compounds simply taste bad (such as in mustard), but other compounds are toxic, or breakdown into toxic compounds within the digestive system. Children, being smaller than adults, are more susceptible to poisoning or death by plants and seeds.[19] One should be satisfied with reliable food safety information before choosing to eat any particular seeds. An infamously deadly poison, ricin, comes from seeds of the castor bean. Reported lethal doses are anywhere from two to eight seeds,[20][21] though only a few deaths have been reported when castor beans have been ingested by animals.[22] In addition, seeds containing amygdalin; apple, apricot, bitter almond,[23] peach, plum, cherry, quince, and others, when consumed in significant amounts, may result in cyanide toxicity[23].[24] Other seeds than contain poisons include annona, cotton, custard apple, datura, uncooked durian, golden chain, horse-chestnut, larkspur, locoweed, lychee, nectarine, rambutan, rosary pea, sour sop, sugar apple, wisteria, and yew.[25][26] Another seed poison is strychnine. The seeds of many legumes, including the common bean (Phaseolus vulgaris) contain proteins called lectins which can cause gastric distress if the beans are eaten without cooking. The common bean and many others, including the soybean, also contain trypsin inhibitors which interfere with the action of the digestive enzyme trypsin. Normal cooking processes degrade lectins and trypsin inhibitors to harmless forms.[27] ## Other uses The world's most important clothing fiber grows attached to cotton seed. Other seed fibers are from kapok and milkweed. Many important nonfood oils are extracted from seeds. Linseed oil is used in paints. Oil from jojoba and crambe are similar to whale oil. Seeds are the source of some medicines including castor oil, tea tree oil and the discredited cancer drug, Laetrile. Many seeds have been used as beads in necklaces and rosaries including Job's tears, Chinaberry and rosary pea. However, the latter two are also poisonous. Other seed uses include: - Seeds once used as weights for balances. - Seeds used as toys by children, such as for the game conker. - Resin from Clusia rosea seeds used to caulk boats. - Nematicide from milkweed seeds. - Cottonseed meal used as animal feed and fertilizer. # Trivia - The oldest viable carbon-14-dated seed that has grown into a plant was a Judean date palm seed about 2,000 years old, recovered from excavations at Herod the Great's palace on Masada in Israel. It was germinated in 2005. [28] - The largest seed is produced by the coco de mer, or "double coconut palm", Lodoicea maldivica. The entire fruit may weigh up to 23 kilograms (50 pounds) and usually contains a single seed.[29] - The earliest fossil seeds are around 365 million years old from the Late Devonian of West Virginia. The seeds are preserved immature ovules of the plant Elkinsia polymorpha.[30]

https://www.wikidoc.org/index.php/Seed

42429b2d8c9491613874a3400cadeff617e0b151

wikidoc

Shq1

Shq1 Shq1p is a protein involved in the rRNA processing pathway. It was discovered by Pok Yang in the Chanfreau labratory at UCLA. Depletion of Shq1p has led to decreased level of various H/ACA box snoRNAs (H/ACA box snoRNAs are responsible for pseuduridylation of pre-rRNA) and certain pre-rRNA intermediates. # Background During the synthesis of eukaryotic ribosomes, four mature ribosomal RNAs (the 5S, 5.8S, 18S, and 25S) must be synthesized. Three of these rRNAs (5.8S, 18S, and 25S) come from a single pre-rRNA known as the 35S. Although many of the intermediates in this rRNA processing pathway have been identified in the last thirty years, there are still a number of proteins involved in this process whose specific function is unknown. Shq1p, a protein thought to play a role in the stablization and/or production of box H/ACA snoRNA, is still uncharacterized. It has been proposed that Shq1p, along with Naf1p, is involved in the initial steps of the biogenesis of H/ACA box snoRNPs (box H/ACA snoRNAs form complexes with proteins, thereby forming snoRNPs) because of its association with certain snoRNP proteins during the snoRNP’s maturation, while showing very little association with the mature snoRNP. Despite the known involvement of Shq1p with the H/ACA box snoRNP's production, the exact function of this protein in the overall rRNA processing pathway is still unknown.

Shq1 Shq1p is a protein involved in the rRNA processing pathway. It was discovered by Pok Yang in the Chanfreau labratory at UCLA. Depletion of Shq1p has led to decreased level of various H/ACA box snoRNAs (H/ACA box snoRNAs are responsible for pseuduridylation of pre-rRNA) and certain pre-rRNA intermediates.[1] # Background During the synthesis of eukaryotic ribosomes, four mature ribosomal RNAs (the 5S, 5.8S, 18S, and 25S) must be synthesized. Three of these rRNAs (5.8S, 18S, and 25S) come from a single pre-rRNA known as the 35S. Although many of the intermediates in this rRNA processing pathway have been identified in the last thirty years, there are still a number of proteins involved in this process whose specific function is unknown. Shq1p, a protein thought to play a role in the stablization and/or production of box H/ACA snoRNA, is still uncharacterized. It has been proposed that Shq1p, along with Naf1p, is involved in the initial steps of the biogenesis of H/ACA box snoRNPs (box H/ACA snoRNAs form complexes with proteins, thereby forming snoRNPs) because of its association with certain snoRNP proteins during the snoRNP’s maturation, while showing very little association with the mature snoRNP. Despite the known involvement of Shq1p with the H/ACA box snoRNP's production, the exact function of this protein in the overall rRNA processing pathway is still unknown.

https://www.wikidoc.org/index.php/Shq1

5f4a4e14e2ae1d815bca6913d5fe0a7ae66ab16b

wikidoc

Slug

Slug # Overview Slug is a common non-scientific word which is most often applied to any gastropod mollusk whatsoever that has a very reduced shell, a small internal shell, or no shell at all. A slug-like body is an adaptation which has occurred many times in various groups of snails. The common name "slug" is most often applied to land species, but the word has also been applied to many marine species. The largest group of marine shell-less gastropods or sea slugs are the nudibranchs, but there are in addition many other groups of sea slug such as the heterobranch sea butterflies, sea angels, and sea hares, as well as the only very distantly related, pelagic, caenogastropod sea slugs, which are within the superfamily Carinarioidea. Evolutionarily speaking, the loss or reduction of the shell in gastropods is a derived characteristic; the same basic body design has independently evolved several times, making slugs a strikingly polyphyletic group. In other words, the shell-less condition has arisen many times in the evolutionary past, and because of this, the various different taxonomic families of slugs are often not at all closely related to one another, despite a superficial similarity. This article is primarily about pulmonate land slugs. # Land slugs Although land slugs have undergone torsion (180º twisting of the internal organs) during development, their bodies are streamlined and worm-like, and so externally they show only a little evidence of this asymmetry, and that mainly in the positioning of the pneumostome. The soft, slimy bodies of slugs are prone to desiccation, so land-living slugs are confined to moist environments. ## Morphology and behaviour Slugs macerate food using their radula, a rough, tongue-like organ with many tiny tooth-like denticles. Like snails, most slugs have two pairs of 'feelers' or tentacles on their head; the upper pair being light sensors, while the lower pair provides the sense of smell. Both pairs are retractable and can be regrown if lost. On top of the slug, behind the head, is the saddle-shaped mantle, and under this are the genital opening and anus. The mantle also has a hole, the pneumostome, for respiration. The slug moves by rhythmic muscular action of its foot. Some species hibernate underground during the winter in temperate climates, but in other species, the adults die in the autumn. ## Mucus Slugs' bodies are made up mostly of water and are prone to desiccation. They must generate protective mucus to survive. In drought conditions they hide under fallen logs, rocks, plants, and planters in order to help retain body moisture. Slugs produce two types of mucus: one which is thin and watery, and another which is thick and sticky. Both are hygroscopic. The thin mucus is spread out from the centre of the foot to the edges. The thick mucus spreads out from front to back. Mucus is very important to slugs because it helps them move around, and contains fibres which prevent the slug from sliding down vertical surfaces. Mucus also provides protection against predators and helps retain moisture. Some species use slime cords to lower themselves on to the ground, or to suspend a pair of slugs during copulation. ## Reproduction Slugs are hermaphrodites, having both female and male reproductive organs. Once a slug has located a mate they encircle each other and sperm is exchanged through their protruding genitalia. A few days later around 30 eggs are laid into a hole in the ground or under the cover of objects such as fallen logs. A commonly seen practice among many slugs is apophallation, when one or both of the slugs chews off the other's penis. The penis of these species is curled like a cork-screw and often becomes entangled in their mate's genitalia in the process of exchanging sperm. When all else fails, apophallation allows the slugs to separate themselves. Once its penis has been removed, a slug is still able to participate in mating subsequently, but only using the female parts of its reproductive system. ## Ecology Many species of slugs play an important role in ecology by eating dead leaves, fungus, and decaying vegetable material. Some slugs are predators. Most slugs will also eat carrion including dead of their own kind. ## Predators Frogs, toads, snakes, hedgehogs, eastern box turtles, and also some birds and beetles are natural slug predators. Slugs, when attacked, can contract their body, making themselves harder and more compact and thus more difficult for many animals to grasp. The unpleasant taste of the mucus is also a deterrent. ## Human relevance A small number of species of slugs feed on fruits and vegetables prior to harvest, making holes in the crop that makes it more vulnerable to rot and disease, and making individual items unsuitable to sell. Slugs such as Deroceras reticulatum are a serious pest to agriculture. In a few cases, humans have contracted parasite-induced meningitis from eating raw slugs . The banana slug, Ariolimax dolichophallus, is the mascot of the University of California at Santa Cruz. # Photographs - Red slug, Arion rufus - red color form on a rhubarb leaf, in England - Banana slug, Ariolimax columbianus, Univ. of Calif. Santa Cruz - Great grey slug, Limax maximus, in Illinois, USA - Two Great grey slugs mating - Tropical leatherleaf, Laevicaulis alte - A slug from North Bend, Washington, USA - A slug from the Western Ghats of India - A slug found in Hampshire, England, feeding on a leaf. - Close up of mating Great Grey Slug found in Maryland, USA - Mating Great Grey Slug found in Maryland, USA - Great Grey Slug pictured in Maryland, USA # Subinfraorders, superfamilies, and families - Subinfraorder Orthurethra Superfamily Achatinelloidea Gulick, 1873 Superfamily Cochlicopoidea Pilsbry, 1900 Superfamily Partuloidea Pilsbry, 1900 Superfamily Pupilloidea Turton, 1831 - Superfamily Achatinelloidea Gulick, 1873 - Superfamily Cochlicopoidea Pilsbry, 1900 - Superfamily Partuloidea Pilsbry, 1900 - Superfamily Pupilloidea Turton, 1831 - Subinfraorder Sigmurethra Superfamily Acavoidea Pilsbry, 1895 Superfamily Achatinoidea Swainson, 1840 Superfamily Aillyoidea Baker, 1960 Superfamily Arionoidea J.E. Gray in Turnton, 1840 Superfamily Athoracophoroidea Family Athoracophoridae Superfamily Buliminoidea Clessin, 1879 Family Bulimulidae Superfamily Camaenoidea Pilsbry, 1895 Superfamily Clausilioidea Mörch, 1864 Superfamily Dyakioidea Gude & Woodward, 1921 Superfamily Gastrodontoidea Tryon, 1866 Superfamily Helicoidea Rafinesque, 1815 Superfamily Helixarionoidea Bourguignat, 1877 Superfamily Limacoidea Rafinesque, 1815 Superfamily Oleacinoidea H. & A. Adams, 1855 Superfamily Orthalicoidea Albers-Martens, 1860 Superfamily Plectopylidoidea Moellendorf, 1900 Superfamily Polygyroidea Pilsbry, 1894 Superfamily Punctoidea Morse, 1864 Superfamily Rhytidoidea Pilsbry, 1893 Family Rhytididae Superfamily Sagdidoidera Pilsbry, 1895 Superfamily Staffordioidea Thiele, 1931 Superfamily Streptaxoidea J.E. Gray, 1806 Superfamily Strophocheiloidea Thiele, 1926 Superfamily Trigonochlamydoidea Hese, 1882 Superfamily Zonitoidea Mörch, 1864 - Superfamily Acavoidea Pilsbry, 1895 - Superfamily Achatinoidea Swainson, 1840 - Superfamily Aillyoidea Baker, 1960 - Superfamily Arionoidea J.E. Gray in Turnton, 1840 - Superfamily Athoracophoroidea Family Athoracophoridae - Family Athoracophoridae - Superfamily Buliminoidea Clessin, 1879 Family Bulimulidae - Family Bulimulidae - Superfamily Camaenoidea Pilsbry, 1895 - Superfamily Clausilioidea Mörch, 1864 - Superfamily Dyakioidea Gude & Woodward, 1921 - Superfamily Gastrodontoidea Tryon, 1866 - Superfamily Helicoidea Rafinesque, 1815 - Superfamily Helixarionoidea Bourguignat, 1877 - Superfamily Limacoidea Rafinesque, 1815 - Superfamily Oleacinoidea H. & A. Adams, 1855 - Superfamily Orthalicoidea Albers-Martens, 1860 - Superfamily Plectopylidoidea Moellendorf, 1900 - Superfamily Polygyroidea Pilsbry, 1894 - Superfamily Punctoidea Morse, 1864 - Superfamily Rhytidoidea Pilsbry, 1893 Family Rhytididae - Family Rhytididae - Superfamily Sagdidoidera Pilsbry, 1895 - Superfamily Staffordioidea Thiele, 1931 - Superfamily Streptaxoidea J.E. Gray, 1806 - Superfamily Strophocheiloidea Thiele, 1926 - Superfamily Trigonochlamydoidea Hese, 1882 - Superfamily Zonitoidea Mörch, 1864

Slug Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Slug is a common non-scientific word which is most often applied to any gastropod mollusk whatsoever that has a very reduced shell, a small internal shell, or no shell at all. A slug-like body is an adaptation which has occurred many times in various groups of snails. The common name "slug" is most often applied to land species, but the word has also been applied to many marine species. The largest group of marine shell-less gastropods or sea slugs are the nudibranchs, but there are in addition many other groups of sea slug such as the heterobranch sea butterflies, sea angels, and sea hares, as well as the only very distantly related, pelagic, caenogastropod sea slugs, which are within the superfamily Carinarioidea. Evolutionarily speaking, the loss or reduction of the shell in gastropods is a derived characteristic; the same basic body design has independently evolved several times, making slugs a strikingly polyphyletic group. In other words, the shell-less condition has arisen many times in the evolutionary past, and because of this, the various different taxonomic families of slugs are often not at all closely related to one another, despite a superficial similarity. This article is primarily about pulmonate land slugs. # Land slugs Although land slugs have undergone torsion (180º twisting of the internal organs) during development, their bodies are streamlined and worm-like, and so externally they show only a little evidence of this asymmetry, and that mainly in the positioning of the pneumostome. The soft, slimy bodies of slugs are prone to desiccation, so land-living slugs are confined to moist environments. ## Morphology and behaviour Slugs macerate food using their radula, a rough, tongue-like organ with many tiny tooth-like denticles. Like snails, most slugs have two pairs of 'feelers' or tentacles on their head; the upper pair being light sensors, while the lower pair provides the sense of smell. Both pairs are retractable and can be regrown if lost. On top of the slug, behind the head, is the saddle-shaped mantle, and under this are the genital opening and anus. The mantle also has a hole, the pneumostome, for respiration. The slug moves by rhythmic muscular action of its foot. Some species hibernate underground during the winter in temperate climates, but in other species, the adults die in the autumn. ## Mucus Slugs' bodies are made up mostly of water and are prone to desiccation. They must generate protective mucus to survive. In drought conditions they hide under fallen logs, rocks, plants, and planters in order to help retain body moisture. Slugs produce two types of mucus: one which is thin and watery, and another which is thick and sticky. Both are hygroscopic. The thin mucus is spread out from the centre of the foot to the edges. The thick mucus spreads out from front to back. Mucus is very important to slugs because it helps them move around, and contains fibres which prevent the slug from sliding down vertical surfaces. Mucus also provides protection against predators and helps retain moisture. Some species use slime cords to lower themselves on to the ground, or to suspend a pair of slugs during copulation. ## Reproduction Slugs are hermaphrodites, having both female and male reproductive organs. Once a slug has located a mate they encircle each other and sperm is exchanged through their protruding genitalia. A few days later around 30 eggs are laid into a hole in the ground or under the cover of objects such as fallen logs. A commonly seen practice among many slugs is apophallation, when one or both of the slugs chews off the other's penis. The penis of these species is curled like a cork-screw and often becomes entangled in their mate's genitalia in the process of exchanging sperm. When all else fails, apophallation allows the slugs to separate themselves. Once its penis has been removed, a slug is still able to participate in mating subsequently, but only using the female parts of its reproductive system. ## Ecology Many species of slugs play an important role in ecology by eating dead leaves, fungus, and decaying vegetable material. Some slugs are predators. Most slugs will also eat carrion including dead of their own kind. ## Predators Frogs, toads, snakes, hedgehogs, eastern box turtles, and also some birds and beetles are natural slug predators. Slugs, when attacked, can contract their body, making themselves harder and more compact and thus more difficult for many animals to grasp. The unpleasant taste of the mucus is also a deterrent. ## Human relevance A small number of species of slugs feed on fruits and vegetables prior to harvest, making holes in the crop that makes it more vulnerable to rot and disease, and making individual items unsuitable to sell. Slugs such as Deroceras reticulatum are a serious pest to agriculture. In a few cases, humans have contracted parasite-induced meningitis from eating raw slugs [1]. The banana slug, Ariolimax dolichophallus, is the mascot of the University of California at Santa Cruz. # Photographs - Red slug, Arion rufus - red color form on a rhubarb leaf, in England - Banana slug, Ariolimax columbianus, Univ. of Calif. Santa Cruz - Great grey slug, Limax maximus, in Illinois, USA - Two Great grey slugs mating - Tropical leatherleaf, Laevicaulis alte - A slug from North Bend, Washington, USA - A slug from the Western Ghats of India - A slug found in Hampshire, England, feeding on a leaf. - Close up of mating Great Grey Slug found in Maryland, USA - Mating Great Grey Slug found in Maryland, USA - Great Grey Slug pictured in Maryland, USA # Subinfraorders, superfamilies, and families - Subinfraorder Orthurethra Superfamily Achatinelloidea Gulick, 1873 Superfamily Cochlicopoidea Pilsbry, 1900 Superfamily Partuloidea Pilsbry, 1900 Superfamily Pupilloidea Turton, 1831 - Superfamily Achatinelloidea Gulick, 1873 - Superfamily Cochlicopoidea Pilsbry, 1900 - Superfamily Partuloidea Pilsbry, 1900 - Superfamily Pupilloidea Turton, 1831 - Subinfraorder Sigmurethra Superfamily Acavoidea Pilsbry, 1895 Superfamily Achatinoidea Swainson, 1840 Superfamily Aillyoidea Baker, 1960 Superfamily Arionoidea J.E. Gray in Turnton, 1840 Superfamily Athoracophoroidea Family Athoracophoridae Superfamily Buliminoidea Clessin, 1879 Family Bulimulidae Superfamily Camaenoidea Pilsbry, 1895 Superfamily Clausilioidea Mörch, 1864 Superfamily Dyakioidea Gude & Woodward, 1921 Superfamily Gastrodontoidea Tryon, 1866 Superfamily Helicoidea Rafinesque, 1815 Superfamily Helixarionoidea Bourguignat, 1877 Superfamily Limacoidea Rafinesque, 1815 Superfamily Oleacinoidea H. & A. Adams, 1855 Superfamily Orthalicoidea Albers-Martens, 1860 Superfamily Plectopylidoidea Moellendorf, 1900 Superfamily Polygyroidea Pilsbry, 1894 Superfamily Punctoidea Morse, 1864 Superfamily Rhytidoidea Pilsbry, 1893 Family Rhytididae Superfamily Sagdidoidera Pilsbry, 1895 Superfamily Staffordioidea Thiele, 1931 Superfamily Streptaxoidea J.E. Gray, 1806 Superfamily Strophocheiloidea Thiele, 1926 Superfamily Trigonochlamydoidea Hese, 1882 Superfamily Zonitoidea Mörch, 1864 - Superfamily Acavoidea Pilsbry, 1895 - Superfamily Achatinoidea Swainson, 1840 - Superfamily Aillyoidea Baker, 1960 - Superfamily Arionoidea J.E. Gray in Turnton, 1840 - Superfamily Athoracophoroidea Family Athoracophoridae - Family Athoracophoridae - Superfamily Buliminoidea Clessin, 1879 Family Bulimulidae - Family Bulimulidae - Superfamily Camaenoidea Pilsbry, 1895 - Superfamily Clausilioidea Mörch, 1864 - Superfamily Dyakioidea Gude & Woodward, 1921 - Superfamily Gastrodontoidea Tryon, 1866 - Superfamily Helicoidea Rafinesque, 1815 - Superfamily Helixarionoidea Bourguignat, 1877 - Superfamily Limacoidea Rafinesque, 1815 - Superfamily Oleacinoidea H. & A. Adams, 1855 - Superfamily Orthalicoidea Albers-Martens, 1860 - Superfamily Plectopylidoidea Moellendorf, 1900 - Superfamily Polygyroidea Pilsbry, 1894 - Superfamily Punctoidea Morse, 1864 - Superfamily Rhytidoidea Pilsbry, 1893 Family Rhytididae - Family Rhytididae - Superfamily Sagdidoidera Pilsbry, 1895 - Superfamily Staffordioidea Thiele, 1931 - Superfamily Streptaxoidea J.E. Gray, 1806 - Superfamily Strophocheiloidea Thiele, 1926 - Superfamily Trigonochlamydoidea Hese, 1882 - Superfamily Zonitoidea Mörch, 1864

https://www.wikidoc.org/index.php/Slug

b082331711aaa78d3ba471a69ac9d54031ea942f

wikidoc

Snus

Snus Snus (pronounced Template:IPA) is a moist powder tobacco product that is consumed by placing it under the upper lip for extended periods of time. It was originally developed from powdered snuff that was inhaled through the nostrils. Snus is manufactured and consumed primarily in Sweden and Norway. A version has recently been introduced into the United States and is being test-marketed by two major American tobacco companies as well as one Swedish company. However, the health effects of these new versions of snus have not yet been studied. # Types There are two main types of snus on the market: - originalsnus or lössnus is a loose, moist powder which can be portioned and rolled into a cylindrical or spherical shape with the fingertips or snus portion tool. The end result is often referred to as a pris (pinch) or prilla or prell (slang for pris). - portionssnus, is prepackaged powder in small bags made from the same material as teabags. It comes in smaller quantities than the loose powder but is considered easier to handle (and expectorate) than the loose powder. Swedish snus is made from air dried tobacco from various parts of the world. In earlier times tobacco for making snus used to be laid out for drying in Scania and Mälardalen. Later Kentucky tobaccos were used. The ground tobacco is mixed with water, salt, sodium carbonate and aroma and is prepared through heating, generally via steam. Moist snus contain more than 50% water, and the average use of snus in Sweden is approximately 800 grams (16 units) per person each year. 12% (1,1 million people) of the population in Sweden uses snus Unlike American-sold oral tobacco, snus has not gone through a fermentation process. Snus is sold mainly in Sweden and Norway and Denmark and is being trialed in South Africa, but can be found in outlets in various other countries frequented by Scandinavian tourists like Murmansk in Russia and other Russian Border Towns (Norwegian Border) (with the notable exception of countries in the EU; see below). It is sold in small tins, which in the earlier years were made of porcelain, wood, silver or gold. At the time of writing, portioned snus usually comes in plastic tins of 24g, while loose snus is mostly sold in compressed paper tins with plastic lids, at 50g. Portioned snus is most commonly sold in three different variants, namely mini, normal and maxi/large. The weights may vary, but the most sold snus labels share their weight. Mini portions weigh 0.5g, with 20 pieces per tin. Normal - or standard - portions weigh 1g, with 24 portions per tin, and maxi portions weigh 1.7g, with 17 pieces per tin. The price for the 50g product is approximately €3-€4 in Sweden and €7.50 in Norway as Norwegian taxes are higher. The total production of Swedish snus, mainly for the Scandinavian market, has been reported to be in excess of 300 million units per year. After the Norwegian government in June 2004 implemented a strict indoor smoking ban in public places, sales of snus sky-rocketed and several new variants of the product were put on the Norwegian market. When the Swedish government did the same thing in June 2005, sales of snus also increased dramatically. # Usage and storage The most usual way to consume snus is to place it beneath the upper lip, and keep it there for a time varying from a few minutes to several hours, which varies greatly from person to person. Snus should be stored refrigerated to minimize the formation of nitrosamines. Many users report that cold snus is subjectively better than warm snus, however, this is also from a person to another, since some perfer room tempered. But most snus cans say that snus should not be in anyplace warmer than 8°C. # Health consequences Since snus is not intended nor recommended for inhalation, it does not affect the lungs as cigarettes do, although it does contain more nicotine than cigarettes. Because it is steam-cured, rather than fire-cured like smoking tobacco or other chewing tobacco, it contains lower concentrations of nitrosamines and other carcinogens that form from the partially anaerobic heating of proteins; 2.8 parts per mil for Ettan brand compared to as high as 127.9 parts per mil in American brands, according to a study by the Commonwealth of Massachusetts Department of Health. The World Health Organization (WHO) acknowledges that Swedish men have the lowest rate of lung cancer in Europe, partly due to the low tobacco smoking rate, but does not argue for substituting snus for smoking, citing that the effects of snus still remain unclear. Since the level of carcinogens in snus is not zero, however, it still poses some increased risk for oral cancer. The European Union banned the sale of snus in 1992, after a 1985 WHO study concluded that "oral use of snuffs of the types used in North America and western Europe is carcinogenic to humans", but a WHO committee on tobacco has also acknowledged that evidence is inconclusive regarding health consequences for snus consumers. Only Sweden and EFTA-member Norway are exempt from this ban. A popular movement during the run-up to the 1994 referendum for Sweden's EU membership made exemption from the EU criminalization of snus a condition of the membership treaty. This may be due to taxation reasons. Recent actions by many European governments to limit the use of cigarettes has led to calls to lift the ban on snus, as it is generally considered to be less harmful than cigarette smoke, both to the user and to others. ## Debate among public health researchers There is some debate among public health researchers over the use of "safer" tobacco or nicotine delivery systems, generally dividing along two lines of thought. Most researchers presently are of the "abstinence" belief, believing that no form of tobacco or nicotine use is acceptable or safe, and should be minimized among the population. A minority (primarily in the European Union and Canada) believes in "harm reduction," where the belief is generally that, while it should remain a goal to reduce addiction to nicotine in the population as a whole, the reduction of harm to the health of those who choose to use nicotine should override the need to reduce overall nicotine addiction. For example, some research available today shows that snus use reduces or eliminates the risk of cancers that afflict other users of tobacco products such as "chewing tobacco" (the type primarily used in the United States and Canada, created in a process similar to cigarette tobacco) and cigarettes. It is hypothesized that the widespread use of snus by Swedish men (estimated at 30% of Swedish male ex-smokers, possibly because it is much cheaper than cigarettes), displacing tobacco smoking and other varieties of snuff, is responsible for the incidence of tobacco-related mortality in men being significantly lower in Sweden than any other European country; in contrast, since women are much less likely to use snus, their rate of tobacco-related deaths in Sweden is similar to that in other European countries. There is an increase in the prevalence of hypertension in snus users, so the health effects are not all positive, however. Snus may be less harmful than other tobacco products; according to Kenneth Warner, director of the University of Michigan Tobacco Research Network, Opponents of snus sales maintain that, nevertheless, even the low nitrosamine levels in snus cannot be completely risk free, but snus proponents point out that inasmuch as snus is used as a substitute for smoking or a means to quit smoking, the net overall effect is positive, similar to the effect of nicotine patches, for instance. In addition, rather obviously, this eliminates any exposure to second-hand smoke, further reducing possible harm to other non-tobacco users. This is seen by public health advocates who believe in "harm reduction" as a reason for recommending snus in addition to other nicotine replacement therapies rather than continued use of cancer-causing nicotine delivery systems. This does not, however, eliminate any harm to health caused by the nicotine itself. Current research focuses on possible long-term effects on blood pressure, and possible risk of cancer of the pancreas due to tobacco-specific nitrosamines (TSNAs). TSNAs are the only component of tobacco shown to induce pancreatic cancer in laboratory animals (Rivenson et al. 1988). Nicotine may also exacerbate pancreatic illness, because nicotine stimulates the gastrointestinal tract's production of cholecystokinin, which stimulates pancreatic growth and may be implicated in pancreatic cancer. Thus far the evidence specifically implicating snus in pancreatic cancer is only suggestive. . It should also be noted that the probability of developing pancreatic cancer from cigarettes is higher than the suggested chance of developing pancreatic cancer from snus. # Published peer-reviewed studies - Effect of smokeless tobacco (snus) on smoking and public health in Sweden, October, 2003 (full text) - Broadstock M. Systematic review of the health effects of modified smokeless tobacco products, N Zealand Health Technol Assessment Rep, February 2007 (full text) ## Cardiovascular diseases - Hergens MP, Ahlbom A, Andersson T, Pershagen G. Swedish moist snuff and myocardial infarction among men. Epidemiology. 2005 Jan;16(1):12-6. (full text) - Broadstock M. Systematic review of the health effects of modified smokeless tobacco products, N Zealand Health Technol Assessment Rep, February 2007, p37-56 (full text) ## Diabetes - Influence of smoking and snus on the prevalence and incidence of type 2 diabetes amongst men: the northern Sweden MONICA study, August 2004 (abstract - full text by subscription only) ## Cancer - Juhua Luo MSc, Weimin Ye MD, Kazem Zendehdel MD, Johanna Adami MD, Prof Hans-Olov Adami MD, Prof Paolo Boffetta MD and Prof Olof Nyrén MD Oral use of Swedish moist snuff (snus) and risk for cancer of the mouth, lung, and pancreas in male construction workers: a retrospective cohort study The Lancet, Volume 369, Issue 9578, Pages 2015-2020 (abstract - full text by subscription only) ## Tobacco control - Role of snus (oral moist snuff) in smoking cessation and smoking reduction in Sweden Hans Gilljam & M. Rosaria Galanti, September 2003 (abstract - full text by subscription only) - Tobacco harm reduction: an alternative cessation strategy for inveterate smokers, Brad Rodu & William T. Godshall, December 2006 Harm Reduction Journal # Medical community discussions and reports - Kjell Asplund. Snuffing, Smoking and the risk for heart disease and other vascular diseases. 3rd revised version. ASH Britain; 2002 (full text) - Discussion of Declining smoking in Sweden: is Swedish Match getting the credit for Swedish tobacco control’s efforts?; Tobacco control (BMJ). 2003. - Some practical points on harm reduction: what to tell your lawmaker and what to tell your brother about Swedish snus, Tobacco Control Online, December, 2003 # General media articles - A Smokeless Alternative To Quitting (Unabridged Version), The New York Times, April 6, 2004 - Should Snuff Be Used as a Tool To Quit Smoking?, The Wall Street Journal, September 16, 2006; Page A1.

Snus Snus (pronounced Template:IPA) is a moist powder tobacco product that is consumed by placing it under the upper lip for extended periods of time. It was originally developed from powdered snuff that was inhaled through the nostrils. Snus is manufactured and consumed primarily in Sweden and Norway. A version has recently been introduced into the United States and is being test-marketed by two major American tobacco companies as well as one Swedish company. However, the health effects of these new versions of snus have not yet been studied. # Types There are two main types of snus on the market: - originalsnus or lössnus is a loose, moist powder which can be portioned and rolled into a cylindrical or spherical shape with the fingertips or snus portion tool. The end result is often referred to as a pris (pinch) or prilla or prell (slang for pris). - portionssnus, is prepackaged powder in small bags made from the same material as teabags. It comes in smaller quantities than the loose powder but is considered easier to handle (and expectorate) than the loose powder. Swedish snus is made from air dried tobacco from various parts of the world. In earlier times tobacco for making snus used to be laid out for drying in Scania and Mälardalen. Later Kentucky tobaccos were used. The ground tobacco is mixed with water, salt, sodium carbonate and aroma and is prepared through heating, generally via steam. Moist snus contain more than 50% water, and the average use of snus in Sweden is approximately 800 grams (16 units) per person each year. 12% (1,1 million people) of the population in Sweden uses snus[1] Unlike American-sold oral tobacco, snus has not gone through a fermentation process. Snus is sold mainly in Sweden and Norway and Denmark and is being trialed in South Africa, but can be found in outlets in various other countries frequented by Scandinavian tourists like Murmansk in Russia and other Russian Border Towns (Norwegian Border) (with the notable exception of countries in the EU; see below). It is sold in small tins, which in the earlier years were made of porcelain, wood, silver or gold. At the time of writing, portioned snus usually comes in plastic tins of 24g, while loose snus is mostly sold in compressed paper tins with plastic lids, at 50g. Portioned snus is most commonly sold in three different variants, namely mini, normal and maxi/large. The weights may vary, but the most sold snus labels share their weight. Mini portions weigh 0.5g, with 20 pieces per tin. Normal - or standard - portions weigh 1g, with 24 portions per tin, and maxi portions weigh 1.7g, with 17 pieces per tin. The price for the 50g product is approximately €3-€4 in Sweden and €7.50 in Norway as Norwegian taxes are higher. The total production of Swedish snus, mainly for the Scandinavian market, has been reported to be in excess of 300 million units per year. After the Norwegian government in June 2004 implemented a strict indoor smoking ban in public places, sales of snus sky-rocketed and several new variants of the product were put on the Norwegian market. When the Swedish government did the same thing in June 2005, sales of snus also increased dramatically. # Usage and storage The most usual way to consume snus is to place it beneath the upper lip, and keep it there for a time varying from a few minutes to several hours, which varies greatly from person to person. Snus should be stored refrigerated to minimize the formation of nitrosamines. Many users report that cold snus is subjectively better than warm snus, however, this is also from a person to another, since some perfer room tempered. But most snus cans say that snus should not be in anyplace warmer than 8°C. # Health consequences Since snus is not intended nor recommended for inhalation, it does not affect the lungs as cigarettes do, although it does contain more nicotine than cigarettes. Because it is steam-cured, rather than fire-cured like smoking tobacco or other chewing tobacco, it contains lower concentrations of nitrosamines and other carcinogens that form from the partially anaerobic heating of proteins; 2.8 parts per mil for Ettan brand compared to as high as 127.9 parts per mil in American brands, according to a study by the Commonwealth of Massachusetts Department of Health. The World Health Organization (WHO) acknowledges that Swedish men have the lowest rate of lung cancer in Europe, partly due to the low tobacco smoking rate, but does not argue for substituting snus for smoking, citing that the effects of snus still remain unclear. Since the level of carcinogens in snus is not zero, however, it still poses some increased risk for oral cancer. The European Union banned the sale of snus in 1992, after a 1985 WHO study concluded that "oral use of snuffs of the types used in North America and western Europe is carcinogenic to humans", but a WHO committee on tobacco has also acknowledged that evidence is inconclusive regarding health consequences for snus consumers. Only Sweden and EFTA-member Norway are exempt from this ban. A popular movement during the run-up to the 1994 referendum for Sweden's EU membership made exemption from the EU criminalization of snus a condition of the membership treaty. This may be due to taxation reasons. Recent actions by many European governments to limit the use of cigarettes has led to calls to lift the ban on snus, as it is generally considered to be less harmful than cigarette smoke, both to the user and to others. ## Debate among public health researchers There is some debate among public health researchers over the use of "safer" tobacco or nicotine delivery systems, generally dividing along two lines of thought. Most researchers presently are of the "abstinence" belief, believing that no form of tobacco or nicotine use is acceptable or safe, and should be minimized among the population. A minority (primarily in the European Union and Canada) believes in "harm reduction," where the belief is generally that, while it should remain a goal to reduce addiction to nicotine in the population as a whole, the reduction of harm to the health of those who choose to use nicotine should override the need to reduce overall nicotine addiction. For example, some research[2] available today shows that snus use reduces or eliminates the risk of cancers that afflict other users of tobacco products such as "chewing tobacco" (the type primarily used in the United States and Canada, created in a process similar to cigarette tobacco) and cigarettes. It is hypothesized that the widespread use of snus by Swedish men (estimated at 30% of Swedish male ex-smokers, possibly because it is much cheaper than cigarettes), displacing tobacco smoking and other varieties of snuff, is responsible for the incidence of tobacco-related mortality in men being significantly lower in Sweden than any other European country; in contrast, since women are much less likely to use snus, their rate of tobacco-related deaths in Sweden is similar to that in other European countries. There is an increase in the prevalence of hypertension in snus users, so the health effects are not all positive, however.[citation needed] Snus may be less harmful than other tobacco products; according to Kenneth Warner, director of the University of Michigan Tobacco Research Network, Opponents of snus sales maintain that, nevertheless, even the low nitrosamine levels in snus cannot be completely risk free, but snus proponents point out that inasmuch as snus is used as a substitute for smoking or a means to quit smoking, the net overall effect is positive, similar to the effect of nicotine patches, for instance. In addition, rather obviously, this eliminates any exposure to second-hand smoke, further reducing possible harm to other non-tobacco users. This is seen by public health advocates who believe in "harm reduction" as a reason for recommending snus in addition to other nicotine replacement therapies rather than continued use of cancer-causing nicotine delivery systems. This does not, however, eliminate any harm to health caused by the nicotine itself. Current research focuses on possible long-term effects on blood pressure, and possible risk of cancer of the pancreas due to tobacco-specific nitrosamines (TSNAs). TSNAs are the only component of tobacco shown to induce pancreatic cancer in laboratory animals (Rivenson et al. 1988). Nicotine may also exacerbate pancreatic illness, because nicotine stimulates the gastrointestinal tract's production of cholecystokinin, which stimulates pancreatic growth and may be implicated in pancreatic cancer. Thus far the evidence specifically implicating snus in pancreatic cancer is only suggestive. [4]. It should also be noted that the probability of developing pancreatic cancer from cigarettes is higher than the suggested chance of developing pancreatic cancer from snus.[citation needed] # Published peer-reviewed studies - Effect of smokeless tobacco (snus) on smoking and public health in Sweden, October, 2003 (full text) - Broadstock M. Systematic review of the health effects of modified smokeless tobacco products, N Zealand Health Technol Assessment Rep, February 2007 (full text) ## Cardiovascular diseases - Hergens MP, Ahlbom A, Andersson T, Pershagen G. Swedish moist snuff and myocardial infarction among men. Epidemiology. 2005 Jan;16(1):12-6. (full text) - Broadstock M. Systematic review of the health effects of modified smokeless tobacco products, N Zealand Health Technol Assessment Rep, February 2007, p37-56 (full text) ## Diabetes - Influence of smoking and snus on the prevalence and incidence of type 2 diabetes amongst men: the northern Sweden MONICA study, August 2004 (abstract - full text by subscription only) ## Cancer - Juhua Luo MSc, Weimin Ye MD, Kazem Zendehdel MD, Johanna Adami MD, Prof Hans-Olov Adami MD, Prof Paolo Boffetta MD and Prof Olof Nyrén MD Oral use of Swedish moist snuff (snus) and risk for cancer of the mouth, lung, and pancreas in male construction workers: a retrospective cohort study The Lancet, Volume 369, Issue 9578, Pages 2015-2020 (abstract - full text by subscription only) ## Tobacco control - Role of snus (oral moist snuff) in smoking cessation and smoking reduction in Sweden Hans Gilljam & M. Rosaria Galanti, September 2003 (abstract - full text by subscription only) - Tobacco harm reduction: an alternative cessation strategy for inveterate smokers, Brad Rodu & William T. Godshall, December 2006 Harm Reduction Journal # Medical community discussions and reports - Kjell Asplund. Snuffing, Smoking and the risk for heart disease and other vascular diseases. 3rd revised version. ASH Britain; 2002 (full text) - Discussion of Declining smoking in Sweden: is Swedish Match getting the credit for Swedish tobacco control’s efforts?; Tobacco control (BMJ). 2003. - Some practical points on harm reduction: what to tell your lawmaker and what to tell your brother about Swedish snus, Tobacco Control Online, December, 2003 # General media articles - A Smokeless Alternative To Quitting (Unabridged Version), The New York Times, April 6, 2004 - Should Snuff Be Used as a Tool To Quit Smoking?, The Wall Street Journal, September 16, 2006; Page A1. # External links ## Discussion - SnusOn.com - snus forum Popular snus users web community & discussion forum - The harm reduction Bulletin Board The Eudoxa think tank's Bulletin Board for discussing snus and harm reduction - Dr. Gunilla Bolinder talked about snus (video, in Swedish) ## Articles - Snus article that compares a few online sellers - "Use of Swedish 'snus' is linked to a doubled risk of pancreatic cancer". EurekAlert. May 11, 2007..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} - Hit and Run article on Snus - Editorial: Snus as a Smoking Replacement - Snus - a safer option for smokers Slate, July 10, 2007 da:Snus de:Snus it:Snus nl:Snus no:Snus nn:Snus sl:Snus fi:Nuuska sv:Snus Template:WikiDoc Sources

https://www.wikidoc.org/index.php/Snus

02a74aab8ceaf1ae91c6953d0446555f0dd50373

wikidoc

Sobp

Sobp Sine oculis-binding protein homolog (SOBP) also known as Jackson circler protein 1 (JXC1) is a protein that in humans is encoded by the SOBP gene. The first SOBP gene was identified in Drosophila melanogaster in a yeast two-hybrid screen that used the SIX domain of the Sine oculis protein as bait. In most genomes, which harbor SOBP, the gene is present as a single copy. # Gene In human, the SOBP gene is located at the long arm of chromosome 6 at 6q21 and it spans a physical distance of slightly more than 171kbp. The mRNA is transcribed from seven exons, oriented from centromere to telomere, of which the first six exons build the open-reading-frame. The coding mRNA counts 2,622 nucleotides that encode a protein of 873 amino acids. In the mouse, Sopb is located at chromosome 10 at cytogenetic band 10qB2 covering a physical region of 172kbp. As in humans, the mouse Sobp coding region spans six exons but its open-reading-frame is somewhat shorter, counting 2595 nucleotides that encode a protein of 864 amino acids. The protein features two nuclear localization signals on each at its very amino- and carboxy-terminus, two proline-rich sequences in addition to two domains that are related to the FCS-type zinc finger domain. Furthermore, all SOBP proteins share two highly conserved motifs. # Expression In the mouse, gene expression profiling by RT-PCR showed a wide expression profile in adult and embryonic tissues with strongest expression being in the brain. By RNA in-situ hybridization, Sobp expression in neonatal tissue was demonstrated in spiral ganglion, the sensory and supporting cells of the maculae of saccule and maculae of utricle, and cristae ampullaris. Sobp is also expressed in the inner nuclear layer of the developing retina at E15, the olfactory epithelium, in neurons of the trigeminal ganglion and in cells surrounding the dermal papillae of hair follicles. # Genetics In human, an autosomal recessive mutation causes severe mental retardation with anterior maxillary protrusion and strabismus, named MRAMS syndrome (OMIM #613671). Homozygosity-mapping linked MRAMS syndrome to a 9.8 Mbp region on 6q21. Evaluation of candidate genes within this interval identified a homozygous missense mutation in SOBP in patients with MARMS syndrome. The mutation truncates the SOBP protein near the carboxy-terminus (p.R661X). In the mouse, two spontaneous recessive autosomal mutations occurred independently at The Jackson Laboratory that were named jackson circler (jc). The first mutation occurred in 1970 on the C57BL/6J background, named C57BL/6J-jc and the second occurred in a B6.129S6 background and was named jc2J. Genetic linkage analyses localized the mutations to chromosome 10. Molecular genetic studies aimed to identify the genetic defect in the jc locus demonstrated a small deletion of 10bp in exon 6 of the Sobp gene. The deletion comprises nucleotides c.1346-1355 and leads to a frame-shift of the open reading frame introducing a stop codon at amino acid position 490 (S449fsX490). In the jc2J allele, the mutation is a nonsense transversion of a guanine to a thymidine (c.1894G>T) changing a glycine to a stop codon (p.G632X). # Phenotypes In the mouse, the truncating mutations jc and jc2J lead to profound hearing loss and erratic circling behavior. Specifically, the cochlear duct is shortened, the organ of Corti exhibits supernumerary outer hair cells, mirror image duplications of tunnel of Corti and inner hair cells, as well as ectopic expression of patches of vestibular-like hair cells in Kolliker's organ. The vestibular end organs have a smaller surface area and are thicker.

Sobp Sine oculis-binding protein homolog (SOBP) also known as Jackson circler protein 1 (JXC1) is a protein that in humans is encoded by the SOBP gene.[1][2][3] The first SOBP gene was identified in Drosophila melanogaster in a yeast two-hybrid screen that used the SIX domain of the Sine oculis protein as bait.[4] In most genomes, which harbor SOBP, the gene is present as a single copy. # Gene In human, the SOBP gene is located at the long arm of chromosome 6 at 6q21 and it spans a physical distance of slightly more than 171kbp. The mRNA is transcribed from seven exons, oriented from centromere to telomere, of which the first six exons build the open-reading-frame. The coding mRNA counts 2,622 nucleotides that encode a protein of 873 amino acids. In the mouse, Sopb is located at chromosome 10 at cytogenetic band 10qB2 covering a physical region of 172kbp. As in humans, the mouse Sobp coding region spans six exons but its open-reading-frame is somewhat shorter, counting 2595 nucleotides that encode a protein of 864 amino acids. The protein features two nuclear localization signals on each at its very amino- and carboxy-terminus, two proline-rich sequences in addition to two domains that are related to the FCS-type zinc finger domain. Furthermore, all SOBP proteins share two highly conserved motifs.[3] # Expression In the mouse, gene expression profiling by RT-PCR showed a wide expression profile in adult and embryonic tissues with strongest expression being in the brain. By RNA in-situ hybridization, Sobp expression in neonatal tissue was demonstrated in spiral ganglion, the sensory and supporting cells of the maculae of saccule and maculae of utricle, and cristae ampullaris. Sobp is also expressed in the inner nuclear layer of the developing retina at E15, the olfactory epithelium, in neurons of the trigeminal ganglion and in cells surrounding the dermal papillae of hair follicles. # Genetics In human, an autosomal recessive mutation causes severe mental retardation with anterior maxillary protrusion and strabismus, named MRAMS syndrome (OMIM #613671). Homozygosity-mapping linked MRAMS syndrome to a 9.8 Mbp region on 6q21. Evaluation of candidate genes within this interval identified a homozygous missense mutation in SOBP in patients with MARMS syndrome. The mutation truncates the SOBP protein near the carboxy-terminus (p.R661X). In the mouse, two spontaneous recessive autosomal mutations occurred independently at The Jackson Laboratory that were named jackson circler (jc). The first mutation occurred in 1970 on the C57BL/6J background, named C57BL/6J-jc and the second occurred in a B6.129S6 background and was named jc2J. Genetic linkage analyses localized the mutations to chromosome 10. Molecular genetic studies aimed to identify the genetic defect in the jc locus demonstrated a small deletion of 10bp in exon 6 of the Sobp gene. The deletion comprises nucleotides c.1346-1355 and leads to a frame-shift of the open reading frame introducing a stop codon at amino acid position 490 (S449fsX490). In the jc2J allele, the mutation is a nonsense transversion of a guanine to a thymidine (c.1894G>T) changing a glycine to a stop codon (p.G632X). # Phenotypes In the mouse, the truncating mutations jc and jc2J lead to profound hearing loss and erratic circling behavior. Specifically, the cochlear duct is shortened, the organ of Corti exhibits supernumerary outer hair cells, mirror image duplications of tunnel of Corti and inner hair cells, as well as ectopic expression of patches of vestibular-like hair cells in Kolliker's organ. The vestibular end organs have a smaller surface area and are thicker.

https://www.wikidoc.org/index.php/Sobp

53d029a699cbd792d1a5686ef7ff6220b01434d1

wikidoc

Soil

Soil Soil is the naturally occurring, unconsolidated or loose covering of broken rock particles and decaying organic matter (humus) on the surface of the Earth, capable of supporting life. In simple terms, soil has three components: solid, liquid, and gas. The solid phase is a mixture of mineral and organic matter. Soil particles pack loosely, forming a soil structure filled with voids. The solid phase occupies about half of the soil volume. The remaining void space contains water (liquid) and air (gas). Soil is also known as earth: it is the substance from which our planet takes its name. # Characteristics Soil color is the first impression one has when viewing soil. Striking colors and contrasting patterns are especially memorable. The Red River in Louisiana carries sediment eroded from extensive reddish soils like Port Silt Loam in Oklahoma. Soil color results from chemical and biological weathering. As the primary minerals in parent material weather, the elements combine into new and colorful compounds. Iron forms secondary minerals with a yellow or red color; organic matter decomposes into brown compounds; and manganese, sulfur and nitrogen can form black mineral deposits. Soil structure is the arrangement of soil particles into aggregates. These may have various shapes, sizes and degrees of development or expression. Soil texture refers to sand, silt and clay composition. Sand and silt are the product of physical weathering while clay is the product of chemical weathering. Clay content is particularly influential on soil behavior due to a high retention capacity for nutrients and water. ## Formation Soil formation, or pedogenesis, is the combined effect of physical, chemical, biological, and anthropogenic processes on soil parent material resulting in the formation of soil horizons. Soil is always changing. The long periods over which change occurs and the multiple influences of change mean that simple soils are rare. While soil can achieve relative stability in properties for extended periods of time, the soil life cycle ultimately ends in soil conditions that leave it vulnerable to erosion. Little of the soil continuum of the earth is older than Tertiary and most no older than Pleistocene. Despite the inevitability of soils retrogression and degradation, most soil cycles are long and productive. How the soil "life" cycle proceeds is influenced by at least five classic soil forming factors: regional climate, biotic potential, topography, parent material, and the passage of time. An example of soil development from bare rock occurs on recent lava flows in warm regions under heavy and very frequent rainfall. In such climates plants become established very quickly on basaltic lava, even though there is very little organic material. The plants are supported by the porous rock becoming filled with nutrient bearing water, for example carrying dissolved bird droppings or guano. The developing plant roots themselves gradually breaks up the porous lava and organic matter soon accumulates but, even before it does, the predominantly porous broken lava in which the plant roots grow can be considered a soil. ## In nature Biogeography is the study of spatial variations in biological communities. Soils are a restricting factor as to what plants can grow in which environments. Soil scientists survey soils in the hope of understanding controls as to what vegetation can and will grow in a particular location Geologists also have a particular interest in the patterns of soil on the surface of the earth. Soil texture, color and chemistry often reflect the underlying geologic parent material and soil types often change at geologic unit boundaries. Buried paleosols mark previous land surfaces and record climatic conditions from previous eras. Geologists use this paleopedological record to understand the ecological relationships in past ecosystems. According to the theory of biorhexistasy, prolonged conditions conducive to forming deep, weathered soils result in increasing ocean salinity and the formation of limestone. Geologists use soil profile features to establish the duration of surface stability in the context of geologic faults or slope stability. An offset subsoil horizon indicates rupture during soil formation and the degree of subsequent subsoil formation is relied upon to establish time since rupture. Soil examined in shovel test pits is used by archaeologists for relative dating based on stratigraphy (as opposed to absolute dating). What is considered most typical is to use soil profile features to determine the maximum reasonable pit depth than needs to be examined for archaeological evidence in the interest of cultural resources management. Soils altered or formed by man (anthropic and anthropogenic soils) are also of interest to archaeologists. An example is Terra preta do Indio. # Uses Soil material is a critical component in the mining and construction industries. Soil serves as a foundation for most construction projects. Massive volumes of soil can be involved in surface mining, road building, and dam construction. Earth sheltering is the architectural practice of using soil for external thermal mass against building walls. Soil resources are critical to the environment, as well as to food and fiber production. Soil provides minerals and water to plants. Soil absorbs rainwater and releases it later thus preventing floods and drought. Soil cleans the water as it percolates. Soil is the habitat for many organisms. Waste management often has a soil component. Septic drain fields treat septic tank effluent uses aerobic soil processes. Landfills use soil for daily cover. Organic soils, especially peat, serve as a significant fuel resource. Both humans in many cultures and animals occasionally eat soil. # Degradation Land degradation is a human induced or natural process which impairs the capacity of land to function. Soils are the critical component in land degradation when it involves acidification, contamination, desertification, erosion, or salination. While soil acidification of alkaline soils is beneficial, it degrades land when soil acidity lowers crop productivity and increases soil vulnerability to contamination and erosion. Soils are often initially acid because their parent materials were acid and initially low in the basic cations (calcium, magnesium, potassium, and sodium). Acidification occurs when these elements are removed from the soil profile by normal rainfall or the harvesting of crops. Soil acidification is accelerated by the use of acid-forming nitrogenous fertilizers and by the effects of acid precipitation. Soil contamination at low levels are often within soil capacity to treat and assimilate. Many waste treatment processes rely on this treatment capacity. Exceeding treatment capacity can damage soil biota and limit soil function. Derelict soils occur where industrial contamination or other development activity damages the soil to such a degree that the land cannot be used safely or productively. Remediation of derelict soil uses principles of geology, physics, chemistry, and biology to degrade, attenuate, isolate, or remove soil contaminants and to restore soil functions and values. Techniques include leaching, air sparging, chemical amendments, phytoremediation, bioremediation, and natural attenuation. Desertification is an environmental process of ecosystem degradation in arid and semi-arid regions, or as a result of human activity. It is a common misconception that droughts cause desertification. Droughts are common in arid and semiarid lands. Well-managed lands can recover from drought when the rains return. Soil management tools include maintaining soil nutrient and organic matter levels, reduced tillage and increased cover. These help to control erosion and maintain productivity during periods when moisture is available. Continued land abuse during droughts, however, increases land degradation. Increased population and livestock pressure on marginal lands accelerates desertification. Soil erosional loss is caused by wind, water, ice, movement in response to gravity. Although the processes may be simultaneous, erosion is distinguished from weathering. Erosion is an intrinsic natural process, but in many places it is increased by human land use. Poor land use practices include deforestation, overgrazing, and improper construction activity. Improved management can limit erosion using techniques like limiting disturbance during construction, avoiding construction during erosion prone periods, intercepting runoff, terrace-building, use of erosion suppressing cover materials and planting trees or other soil binding plants. A serious and long-running water erosion problem is in China, on the middle reaches of the Yellow River and the upper reaches of the Yangtze River. From the Yellow River, over 1.6 billion tons of sediment flow each year into the ocean. The sediment originates primarily from water erosion in the Loess Plateau region of northwest China. Soil piping is a particular form of soil erosion that occurs below the soil surface. It is associated with levee and dam failure as well as sink hole formation. Turbulent flow removes soil starting from the mouth of the seep flow and subsoil erosion advances upgradient. The term sand boil is used to describe the appearance of the discharging end of an active soil pipe. Soil salination is the accumulation of free salts to such an extent that it leads to degradation of soils and vegetation. Consequences include corrosion damage, reduced plant growth, erosion due to loss of plant cover and soil structure, and water quality problems due to sedimentation. Salination occurs due to a combination of natural and human caused processes. Aridic conditions favor salt accumulation. This is especially apparent when soil parent material is saline. Irrigation of arid lands is especially problematic. All irrigation water has some level of salinity. Irrigation, especially when it involves leakage from canals, often raise the underlying water table. Rapid salination occurs when the land surface is within the capillary fringe of saline groundwater. Salinity control involves flushing with higher levels of applied water in combination with tile drainage..

Soil Soil is the naturally occurring, unconsolidated or loose covering of broken rock particles and decaying organic matter (humus) on the surface of the Earth, capable of supporting life.[1] In simple terms, soil has three components: solid, liquid, and gas. The solid phase is a mixture of mineral and organic matter. Soil particles pack loosely, forming a soil structure filled with voids.[2] The solid phase occupies about half of the soil volume. The remaining void space contains water (liquid) and air (gas).[3] Soil is also known as earth: it is the substance from which our planet takes its name. # Characteristics Soil color is the first impression one has when viewing soil. Striking colors and contrasting patterns are especially memorable. The Red River in Louisiana carries sediment eroded from extensive reddish soils like Port Silt Loam in Oklahoma. Soil color results from chemical and biological weathering. As the primary minerals in parent material weather, the elements combine into new and colorful compounds. Iron forms secondary minerals with a yellow or red color; organic matter decomposes into brown compounds; and manganese, sulfur and nitrogen can form black mineral deposits. [4] Soil structure is the arrangement of soil particles into aggregates. These may have various shapes, sizes and degrees of development or expression.[5] Soil texture refers to sand, silt and clay composition. Sand and silt are the product of physical weathering while clay is the product of chemical weathering. Clay content is particularly influential on soil behavior due to a high retention capacity for nutrients and water.[6] ## Formation Soil formation, or pedogenesis, is the combined effect of physical, chemical, biological, and anthropogenic processes on soil parent material resulting in the formation of soil horizons. Soil is always changing. The long periods over which change occurs and the multiple influences of change mean that simple soils are rare. While soil can achieve relative stability in properties for extended periods of time, the soil life cycle ultimately ends in soil conditions that leave it vulnerable to erosion. Little of the soil continuum of the earth is older than Tertiary and most no older than Pleistocene.[7] Despite the inevitability of soils retrogression and degradation, most soil cycles are long and productive. How the soil "life" cycle proceeds is influenced by at least five classic soil forming factors: regional climate, biotic potential, topography, parent material, and the passage of time. An example of soil development from bare rock occurs on recent lava flows in warm regions under heavy and very frequent rainfall. In such climates plants become established very quickly on basaltic lava, even though there is very little organic material. The plants are supported by the porous rock becoming filled with nutrient bearing water, for example carrying dissolved bird droppings or guano. The developing plant roots themselves gradually breaks up the porous lava and organic matter soon accumulates but, even before it does, the predominantly porous broken lava in which the plant roots grow can be considered a soil. ## In nature Biogeography is the study of spatial variations in biological communities. Soils are a restricting factor as to what plants can grow in which environments. Soil scientists survey soils in the hope of understanding controls as to what vegetation can and will grow in a particular location Geologists also have a particular interest in the patterns of soil on the surface of the earth. Soil texture, color and chemistry often reflect the underlying geologic parent material and soil types often change at geologic unit boundaries. Buried paleosols mark previous land surfaces and record climatic conditions from previous eras. Geologists use this paleopedological record to understand the ecological relationships in past ecosystems. According to the theory of biorhexistasy, prolonged conditions conducive to forming deep, weathered soils result in increasing ocean salinity and the formation of limestone. Geologists use soil profile features to establish the duration of surface stability in the context of geologic faults or slope stability. An offset subsoil horizon indicates rupture during soil formation and the degree of subsequent subsoil formation is relied upon to establish time since rupture. Soil examined in shovel test pits is used by archaeologists for relative dating based on stratigraphy (as opposed to absolute dating). What is considered most typical is to use soil profile features to determine the maximum reasonable pit depth than needs to be examined for archaeological evidence in the interest of cultural resources management. Soils altered or formed by man (anthropic and anthropogenic soils) are also of interest to archaeologists. An example is Terra preta do Indio. # Uses Template:Expand-section Soil material is a critical component in the mining and construction industries. Soil serves as a foundation for most construction projects. Massive volumes of soil can be involved in surface mining, road building, and dam construction. Earth sheltering is the architectural practice of using soil for external thermal mass against building walls. Soil resources are critical to the environment, as well as to food and fiber production. Soil provides minerals and water to plants. Soil absorbs rainwater and releases it later thus preventing floods and drought. Soil cleans the water as it percolates. Soil is the habitat for many organisms. Waste management often has a soil component. Septic drain fields treat septic tank effluent uses aerobic soil processes. Landfills use soil for daily cover. Organic soils, especially peat, serve as a significant fuel resource. Both humans in many cultures and animals occasionally eat soil. # Degradation Land degradation is a human induced or natural process which impairs the capacity of land to function. Soils are the critical component in land degradation when it involves acidification, contamination, desertification, erosion, or salination. While soil acidification of alkaline soils is beneficial, it degrades land when soil acidity lowers crop productivity and increases soil vulnerability to contamination and erosion. Soils are often initially acid because their parent materials were acid and initially low in the basic cations (calcium, magnesium, potassium, and sodium). Acidification occurs when these elements are removed from the soil profile by normal rainfall or the harvesting of crops. Soil acidification is accelerated by the use of acid-forming nitrogenous fertilizers and by the effects of acid precipitation. Soil contamination at low levels are often within soil capacity to treat and assimilate. Many waste treatment processes rely on this treatment capacity. Exceeding treatment capacity can damage soil biota and limit soil function. Derelict soils occur where industrial contamination or other development activity damages the soil to such a degree that the land cannot be used safely or productively. Remediation of derelict soil uses principles of geology, physics, chemistry, and biology to degrade, attenuate, isolate, or remove soil contaminants and to restore soil functions and values. Techniques include leaching, air sparging, chemical amendments, phytoremediation, bioremediation, and natural attenuation. Desertification is an environmental process of ecosystem degradation in arid and semi-arid regions, or as a result of human activity. It is a common misconception that droughts cause desertification. Droughts are common in arid and semiarid lands. Well-managed lands can recover from drought when the rains return. Soil management tools include maintaining soil nutrient and organic matter levels, reduced tillage and increased cover. These help to control erosion and maintain productivity during periods when moisture is available. Continued land abuse during droughts, however, increases land degradation. Increased population and livestock pressure on marginal lands accelerates desertification. Soil erosional loss is caused by wind, water, ice, movement in response to gravity. Although the processes may be simultaneous, erosion is distinguished from weathering. Erosion is an intrinsic natural process, but in many places it is increased by human land use. Poor land use practices include deforestation, overgrazing, and improper construction activity. Improved management can limit erosion using techniques like limiting disturbance during construction, avoiding construction during erosion prone periods, intercepting runoff, terrace-building, use of erosion suppressing cover materials and planting trees or other soil binding plants. A serious and long-running water erosion problem is in China, on the middle reaches of the Yellow River and the upper reaches of the Yangtze River. From the Yellow River, over 1.6 billion tons of sediment flow each year into the ocean. The sediment originates primarily from water erosion in the Loess Plateau region of northwest China. Soil piping is a particular form of soil erosion that occurs below the soil surface. It is associated with levee and dam failure as well as sink hole formation. Turbulent flow removes soil starting from the mouth of the seep flow and subsoil erosion advances upgradient.[8] The term sand boil is used to describe the appearance of the discharging end of an active soil pipe.[9] Soil salination is the accumulation of free salts to such an extent that it leads to degradation of soils and vegetation. Consequences include corrosion damage, reduced plant growth, erosion due to loss of plant cover and soil structure, and water quality problems due to sedimentation. Salination occurs due to a combination of natural and human caused processes. Aridic conditions favor salt accumulation. This is especially apparent when soil parent material is saline. Irrigation of arid lands is especially problematic. All irrigation water has some level of salinity. Irrigation, especially when it involves leakage from canals, often raise the underlying water table. Rapid salination occurs when the land surface is within the capillary fringe of saline groundwater. Salinity control involves flushing with higher levels of applied water in combination with tile drainage.[10].

https://www.wikidoc.org/index.php/Soil

7533be241941d531d31197b17078fee30f7f682e

wikidoc

Soma

Soma Soma (Sanskrit: सोमः), or Haoma (Avestan), from Proto-Indo-Iranian *sauma-, was a ritual drink of importance among the early Indo-Iranians, and the later Vedic and greater Persian cultures. It is frequently mentioned in the Rigveda, which contains many hymns praising its energizing or intoxicating qualities. In the Avesta, Haoma has an entire Yasht dedicated to it. It is described as prepared by pressing juice from the stalks of a certain mountain plant, which has been variously hypothesized to be a psychedelic mushroom, cannabis, Peganum harmala, Blue lotus, or ephedra. In both Vedic and Zoroastrian tradition, the drink is identified with the plant, and also personified as a divinity, the three forming a religious or mythological unity. # Etymology Both Soma and the Avestan Haoma are derived from Proto-Indo-Iranian *sauma-. The name of the Scythian tribe Hauma-varga is related to the word, and probably connected with the ritual. The word is derived from an Indo-Iranian root *sav- (Sanskrit sav-) "to press", i.e. *sav-ma- is the drink prepared by pressing the stalks of a plant (cf. es-presso). The root is probably Proto-Indo-European (*sewh-), and also appears in son (from *suhnu-, "pressed out" i.e. "newly born"). # Vedic Soma In the Vedas, Soma is portrayed as sacred and as a god (deva). The god, the drink and the plant probably referred to the same entity, or at least the differentiation was ambiguous. In this aspect, Soma is similar to the Greek ambrosia (cognate to amrita); it is what the gods drink, and what made them deities. Indra and Agni are portrayed as consuming Soma in copious quantities. The consumption of Soma by human beings was probably under the belief that it bestowed divine qualities on them. ### In the Rigveda The Rigveda (8.48.3, tr. Griffith) states, The Ninth Mandala of the Rigveda is known as the Soma Mandala. It consists entirely of hymns addressed to Soma Pavamana ("purified Soma"). The drink Soma was kept and distributed by the Gandharvas. The Rigveda associates the Sushoma, Arjikiya and other regions with Soma (e.g. 8.7.29; 8.64.10-11). Sharyanavat was possibly the name of a pond or lake on the banks of which Soma could be found. The plant is described as growing in the mountains (giristha, cf. Orestes), with long stalks, and of yellow or tawny (hari) colour. The drink is prepared by priests pounding the stalks with stones, an occupation that creates tapas (literally "heat", later referring to "spiritual excitement" in particular). The juice so gathered is mixed with other ingredients (including milk and honey) before it is drunk. Growing far away, in the mountains, Soma had to be purchased from travelling traders. The plant supposedly grew in the Hindukush and thus it had to be imported to the Punjab region. Later, knowledge of the plant was lost altogether, and Indian ritual reflects this, in expiatory prayers apologizing to the gods for the use of a substitute plant (e.g. rhubarb) because Soma had become unavailable. ### In Hinduism In Hindu art, the god Soma was depicted as a bull or bird, and sometimes as an embryo, but rarely as an adult human. In Hinduism, the god Soma evolved into a lunar deity, and became associated with the underworld. The moon is the cup from which the gods drink Soma, and so Soma became identified with the moon god Chandra. A waxing moon meant Soma was recreating himself, ready to be drunk again. Alternatively, Soma's twenty-seven wives were daughters of Daksha, who felt he paid too much attention to just one of his wives, Rohini. He cursed him to wither and die, but the wives intervened and the death became periodic and temporary, and is symbolized by the waxing and waning of the moon. The famous ayurvedic scholar Sushruta wrote that the best Soma is found in the upper Indus and Kashmir region (Sushruta Samhita: 537-538, SS.CS. 29.28-31). # Avestan Haoma The continuing of Haoma in Zoroastrianism may be glimpsed from the Avesta (particularly in the Hōm Yast, Yasna 9.11), and Avestan language *hauma also survived as middle Persian hōm. The plant Haoma yielded the essential ingredient for the ritual drink, parahaoma. In the Hōm yašt of the Avesta, the Yazata (divine) Haoma appears to Zoroaster "at the time of pressing" (havani ratu) in the form of a beautiful man. Yasna 9.1 and 9.2 exhort him to gather and press Haoma plants. Haoma's epitheta include "the Golden-Green One" (zairi-, Sanskrit hari-), "righteous" (ašavan-), "furthering righteousness" (aša-vazah-), and "of good wisdom" (hu.xratu-, Sanskrit sukratu-). In Yasna 9.22, Haoma grants "speed and strength to warriors, excellent and righteous sons to those giving birth, spiritual power and knowledge to those who apply themselves to the study of the nasks". As the religion's chief cult divinity he came to be perceived as its divine priest. In Yasna 9.26, Ahura Mazda is said to have invested him with the sacred girdle, and in Yasna 10.89, to have installed Haoma as the "swiftly sacrificing zaotar" (Sanskrit hotar) for himself and the Amesha Spenta. Haoma services were celebrated until the 1960s in a strongly conservative village near Yazd. # Candidates for the Soma plant There has been much speculation as to the original Proto-Indo-Iranian Sauma plant. It was generally assumed to be hallucinogenic, based on RV 8.48 cited above. But note that this is the only evidence of hallucinogenic properties, in a book full of hymns to Soma. The typical description of Soma is associated with excitation and tapas. Soma is associated with the warrior-god Indra, and appears to have been drunk before battle. For these reasons, there are energizing plants as well as hallucinogenic plants among the candidates that have been suggested, including fly agaric (Amanita muscaria) which was widely used as a brew of sorts among Siberian shamans for its hallucinogenic and 'religious experience'-inducing properties. Several texts like the Atharva Veda extol the medicinal properties of Soma and he is regarded as the king of medicinal herbs (and also of the Brahmana class). Since the late 1700s, when Anquetil-Duperron and others made portions of the Avesta available to western scholarship, several scholars have sought a representative botanical equivalent of the haoma as described in the texts and as used in living Zoroastrian practice. Most of the proposals concentrated on either linguistic evidence or comparative pharmacology or reflected ritual use. Rarely were all three considered together, which usually resulted in such proposals being quickly rejected. In the late 19th century, the highly conservative Zoroastrians of Yazd (Iran) were found to use Ephedra (genus Ephedra), which was locally known as hum or homa and which they exported to the Indian Zoroastrians. (Aitchison, 1888) The plant, as Falk also established, requires a cool and dry climate, i.e. it does not grow in India (which is either too hot or too humid or both) but thrives in central Asia. Later, it was discovered that a number of Iranian languages and Persian dialects have hom or similar terms as the local name for some variant of Ephedra. There are numerous mountain regions in the north west Indian subcontinent which have cool and dry conditions where soma plant can grow. In later vedic texts the mention of best soma plant coming from kashmir has been mentioned. This is also supported by the presence of high concentration of vedic Brahmans in Kashmir up to the present day who setteled there in ancient times because of the easy availability of soma plant. From the late 1960s onwards, several studies attempted to establish soma as a psychotropic substance. A number of proposals were made, included an important one in 1968 by Robert Gordon Wasson, an amateur mycologist, who (on Vedic evidence) asserted that soma was an inebriant, and suggested fly-agaric mushroom, Amanita muscaria, as the likely candidate. Wasson and his co-author, Wendy Doniger O'Flaherty, drew parallels between Vedic descriptions and reports of Siberian uses of the fly-agaric in shamanic ritual. (Wasson, Robert Gordon (1968). "Soma: Divine Mushroom of Immortality". Ethno-Mycological Studies. New York. 1..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}) # In Western culture In Aldous Huxley's dystopian novel Brave New World, Soma is the popular dream-inducing drug which is employed by the government as a method of control through pleasure and immediate availability. It is ordinary among the culture of the novel for everyone to use it for whatever various practices: sex, relaxation, concentration, confidence. It is seemingly a single-chemical combination of many of today's drugs' effects, giving its patients the full hedonistic spectrum. Soma is the central theme of the poem The Brewing of the Soma by the American Quaker poet, John Whittier (1807-1892) from which the well-known Christian hymn "Dear Lord and Father of Mankind" is derived. Whittier here portrays the drinking of soma as distracting the mind from the proper worship of God. Soma has also been frequently referenced in popular culture, see Soma (disambiguation).

Soma Click here for the drug Soma. Soma (Sanskrit: सोमः), or Haoma (Avestan), from Proto-Indo-Iranian *sauma-, was a ritual drink of importance among the early Indo-Iranians, and the later Vedic and greater Persian cultures. It is frequently mentioned in the Rigveda, which contains many hymns praising its energizing or intoxicating qualities. In the Avesta, Haoma has an entire Yasht dedicated to it. It is described as prepared by pressing juice from the stalks of a certain mountain plant, which has been variously hypothesized to be a psychedelic mushroom, cannabis, Peganum harmala, Blue lotus[1], or ephedra. In both Vedic and Zoroastrian tradition, the drink is identified with the plant, and also personified as a divinity, the three forming a religious or mythological unity. # Etymology Both Soma and the Avestan Haoma are derived from Proto-Indo-Iranian *sauma-. The name of the Scythian tribe Hauma-varga is related to the word, and probably connected with the ritual. The word is derived from an Indo-Iranian root *sav- (Sanskrit sav-) "to press", i.e. *sav-ma- is the drink prepared by pressing the stalks of a plant (cf. es-presso). The root is probably Proto-Indo-European (*sewh-), and also appears in son (from *suhnu-, "pressed out" i.e. "newly born"). # Vedic Soma In the Vedas, Soma is portrayed as sacred and as a god (deva). The god, the drink and the plant probably referred to the same entity, or at least the differentiation was ambiguous. In this aspect, Soma is similar to the Greek ambrosia (cognate to amrita); it is what the gods drink, and what made them deities. Indra and Agni are portrayed as consuming Soma in copious quantities. The consumption of Soma by human beings was probably under the belief that it bestowed divine qualities on them. ### In the Rigveda The Rigveda (8.48.3, tr. Griffith) states, The Ninth Mandala of the Rigveda is known as the Soma Mandala. It consists entirely of hymns addressed to Soma Pavamana ("purified Soma"). The drink Soma was kept and distributed by the Gandharvas. The Rigveda associates the Sushoma, Arjikiya and other regions with Soma (e.g. 8.7.29; 8.64.10-11). Sharyanavat was possibly the name of a pond or lake on the banks of which Soma could be found. The plant is described as growing in the mountains (giristha, cf. Orestes), with long stalks, and of yellow or tawny (hari) colour. The drink is prepared by priests pounding the stalks with stones, an occupation that creates tapas (literally "heat", later referring to "spiritual excitement" in particular). The juice so gathered is mixed with other ingredients (including milk and honey) before it is drunk. Growing far away, in the mountains, Soma had to be purchased from travelling traders. The plant supposedly grew in the Hindukush and thus it had to be imported to the Punjab region.[citation needed] Later, knowledge of the plant was lost altogether, and Indian ritual reflects this, in expiatory prayers apologizing to the gods for the use of a substitute plant (e.g. rhubarb) because Soma had become unavailable. ### In Hinduism In Hindu art, the god Soma was depicted as a bull or bird, and sometimes as an embryo, but rarely as an adult human. In Hinduism, the god Soma evolved into a lunar deity, and became associated with the underworld. The moon is the cup from which the gods drink Soma, and so Soma became identified with the moon god Chandra. A waxing moon meant Soma was recreating himself, ready to be drunk again. Alternatively, Soma's twenty-seven wives were daughters of Daksha, who felt he paid too much attention to just one of his wives, Rohini. He cursed him to wither and die, but the wives intervened and the death became periodic and temporary, and is symbolized by the waxing and waning of the moon. The famous ayurvedic scholar Sushruta wrote that the best Soma is found in the upper Indus and Kashmir region (Sushruta Samhita: 537-538, SS.CS. 29.28-31). # Avestan Haoma The continuing of Haoma in Zoroastrianism may be glimpsed from the Avesta (particularly in the Hōm Yast, Yasna 9.11), and Avestan language *hauma also survived as middle Persian hōm. The plant Haoma yielded the essential ingredient for the ritual drink, parahaoma. In the Hōm yašt of the Avesta, the Yazata (divine) Haoma appears to Zoroaster "at the time of pressing" (havani ratu) in the form of a beautiful man. Yasna 9.1 and 9.2 exhort him to gather and press Haoma plants. Haoma's epitheta include "the Golden-Green One" (zairi-, Sanskrit hari-), "righteous" (ašavan-), "furthering righteousness" (aša-vazah-), and "of good wisdom" (hu.xratu-, Sanskrit sukratu-). In Yasna 9.22, Haoma grants "speed and strength to warriors, excellent and righteous sons to those giving birth, spiritual power and knowledge to those who apply themselves to the study of the nasks". As the religion's chief cult divinity he came to be perceived as its divine priest. In Yasna 9.26, Ahura Mazda is said to have invested him with the sacred girdle, and in Yasna 10.89, to have installed Haoma as the "swiftly sacrificing zaotar" (Sanskrit hotar) for himself and the Amesha Spenta. Haoma services were celebrated until the 1960s in a strongly conservative village near Yazd[citation needed]. # Candidates for the Soma plant There has been much speculation as to the original Proto-Indo-Iranian Sauma plant. It was generally assumed to be hallucinogenic, based on RV 8.48 cited above. But note that this is the only evidence of hallucinogenic properties, in a book full of hymns to Soma. The typical description of Soma is associated with excitation and tapas. Soma is associated with the warrior-god Indra, and appears to have been drunk before battle. For these reasons, there are energizing plants as well as hallucinogenic plants among the candidates that have been suggested, including fly agaric (Amanita muscaria) which was widely used as a brew of sorts among Siberian shamans for its hallucinogenic and 'religious experience'-inducing properties. Several texts like the Atharva Veda extol the medicinal properties of Soma and he is regarded as the king of medicinal herbs (and also of the Brahmana class). Since the late 1700s, when Anquetil-Duperron and others made portions of the Avesta available to western scholarship, several scholars have sought a representative botanical equivalent of the haoma as described in the texts and as used in living Zoroastrian practice. Most of the proposals concentrated on either linguistic evidence or comparative pharmacology or reflected ritual use. Rarely were all three considered together, which usually resulted in such proposals being quickly rejected. In the late 19th century, the highly conservative Zoroastrians of Yazd (Iran) were found to use Ephedra (genus Ephedra), which was locally known as hum or homa and which they exported to the Indian Zoroastrians. (Aitchison, 1888) The plant, as Falk also established, requires a cool and dry climate, i.e. it does not grow in India (which is either too hot or too humid or both) but thrives in central Asia. Later, it was discovered that a number of Iranian languages and Persian dialects have hom or similar terms as the local name for some variant of Ephedra. There are numerous mountain regions in the north west Indian subcontinent which have cool and dry conditions where soma plant can grow. In later vedic texts the mention of best soma plant coming from kashmir has been mentioned. This is also supported by the presence of high concentration of vedic Brahmans in Kashmir up to the present day who setteled there in ancient times because of the easy availability of soma plant. From the late 1960s onwards, several studies attempted to establish soma as a psychotropic substance. A number of proposals were made, included an important one in 1968 by Robert Gordon Wasson, an amateur mycologist, who (on Vedic evidence) asserted that soma was an inebriant, and suggested fly-agaric mushroom, Amanita muscaria, as the likely candidate. Wasson and his co-author, Wendy Doniger O'Flaherty, drew parallels between Vedic descriptions and reports of Siberian uses of the fly-agaric in shamanic ritual. (Wasson, Robert Gordon (1968). "Soma: Divine Mushroom of Immortality". Ethno-Mycological Studies. New York. 1..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}) # In Western culture In Aldous Huxley's dystopian novel Brave New World, Soma is the popular dream-inducing drug which is employed by the government as a method of control through pleasure and immediate availability. It is ordinary among the culture of the novel for everyone to use it for whatever various practices: sex, relaxation, concentration, confidence. It is seemingly a single-chemical combination of many of today's drugs' effects, giving its patients the full hedonistic spectrum. Soma is the central theme of the poem The Brewing of the Soma by the American Quaker poet, John Whittier (1807-1892) from which the well-known Christian hymn "Dear Lord and Father of Mankind" is derived. Whittier here portrays the drinking of soma as distracting the mind from the proper worship of God. Soma has also been frequently referenced in popular culture, see Soma (disambiguation).

https://www.wikidoc.org/index.php/Soma

fd6c18aadea6c65feb29a30d6802f362c31fb7eb

wikidoc

Suet

Suet Suet (/ˈsuː.ɪt/) is raw beef or mutton fat, especially the hard fat found around the loins and kidneys. Suet has a melting point of between 45° and 50°C. (113° and 122°F.), and congeals between 37° and 40°C. (98.6° and 104°F.). # Uses The primary use of suet is to make tallow, although it is also used as an ingredient in cooking. Suet is made into tallow in a process called rendering, which involves melting and extended simmering, followed by straining, cooling and usually a repetition of the entire process. Unlike suet, tallow can be stored for extended periods without refrigeration. Tallow is used to make soap, for cooking (fried foods especially), as a bird food, and was once used for making candles. Suet is essential to use in making the pastry for steamed steak and kidney pudding. The suet crust pastry lines a pudding bowl, the meat added and a lid of suet crust pastry tightly seals the meat. The pudding is then steamed for approximately four hours before serving in the bowl on the table. Suet pastry is soft in contrast to the crispness of shortcrust pastry. Its low melting point means that it is solid at room temperature but easily melts at moderate temperatures, such as in steaming. Suet should not be confused with Beef Dripping, which is the collected fat and juices from the roasting pan when cooking roast beef and is not rendered. # Availability As it is the fat from around the kidneys, the connective tissue, blood and other non-fat items must be removed. It then needs to be coarsely grated to make it ready to use. It must be kept refrigerated prior to use and used within a few days of purchase like any meat. Packaged suet sold in supermarkets is dehydrated suet. It is mixed with flour to make it stable at room temperature. Because of the addition of flour, some care is needed when using it for older recipes using fresh suet as the proportions of flour to fat can alter. Most modern recipes would stipulate packaged suet. A vegetarian suet substitute is available in supermarkets in the United Kingdom that is made from fat such as palm oil combined with rice flour. It resembles shredded beef suet, and is used as a substitute in recipes, but with slightly different results from animal suet. Woodpeckers, goldfinches, juncos, cardinals, thrushes, jays, kinglets, bluebirds, wrens, and starlings are all known to favour suet-based bird feeders. # Suet recipes - Haggis - Windsor pudding - Steak and kidney pudding - Dumplings - Suet Crust Pastry - Christmas pudding - Suet Cakes (for birdfeeding) - Mincemeat - Spotted dick - Kishka/Kishke - Chili con carne - Rag Pudding

Suet Suet (/ˈsuː.ɪt/) is raw beef or mutton fat, especially the hard fat found around the loins and kidneys. Suet has a melting point of between 45° and 50°C. (113° and 122°F.), and congeals between 37° and 40°C. (98.6° and 104°F.). # Uses The primary use of suet is to make tallow, although it is also used as an ingredient in cooking. Suet is made into tallow in a process called rendering, which involves melting and extended simmering, followed by straining, cooling and usually a repetition of the entire process. Unlike suet, tallow can be stored for extended periods without refrigeration. Tallow is used to make soap, for cooking (fried foods especially), as a bird food, and was once used for making candles. Suet is essential to use in making the pastry for steamed steak and kidney pudding. The suet crust pastry lines a pudding bowl, the meat added and a lid of suet crust pastry tightly seals the meat. The pudding is then steamed for approximately four hours before serving in the bowl on the table. Suet pastry is soft in contrast to the crispness of shortcrust pastry. Its low melting point means that it is solid at room temperature but easily melts at moderate temperatures, such as in steaming. Suet should not be confused with Beef Dripping, which is the collected fat and juices from the roasting pan when cooking roast beef and is not rendered. # Availability As it is the fat from around the kidneys, the connective tissue, blood and other non-fat items must be removed. It then needs to be coarsely grated to make it ready to use. It must be kept refrigerated prior to use and used within a few days of purchase like any meat. Packaged suet sold in supermarkets is dehydrated suet. It is mixed with flour to make it stable at room temperature. Because of the addition of flour, some care is needed when using it for older recipes using fresh suet as the proportions of flour to fat can alter. Most modern recipes would stipulate packaged suet. A vegetarian suet substitute is available in supermarkets in the United Kingdom that is made from fat such as palm oil combined with rice flour. It resembles shredded beef suet, and is used as a substitute in recipes, but with slightly different results from animal suet. Woodpeckers, goldfinches, juncos, cardinals, thrushes, jays, kinglets, bluebirds, wrens, and starlings are all known to favour suet-based bird feeders.[1] # Suet recipes Template:Nutritionalvalue - Haggis - Windsor pudding - Steak and kidney pudding - Dumplings - Suet Crust Pastry - Christmas pudding - Suet Cakes (for birdfeeding) - Mincemeat - Spotted dick - Kishka/Kishke - Chili con carne - Rag Pudding

https://www.wikidoc.org/index.php/Suet

e168c8547064763b494d33f09d0d762916a6276c

wikidoc

TAC1

TAC1 Preprotachykinin-1, (abbreviated PPT-1, PPT-I, or PPT-A), is a precursor protein that in humans is encoded by the TAC1 gene. # Isoforms and derivatives The protein has four isoforms—alpha-, beta-, gamma-, and delta-PPT—which can variably undergo post-translational modification to produce neurokinin A (formerly known as substance K) and substance P. Alpha- and delta-PPT can only be modified to substance P, whereas beta- and gamma-PPT can produce both substance P and neurokinin A. Neurokinin A can also be further modified to produce neuropeptide K (also known as neurokinin K) and neuropeptide gamma. These hormones are thought to function as neurotransmitters which interact with nerve receptors and smooth muscle cells. They are known to induce behavioral responses and function as vasodilators and secretagogues. Alternative splicing of exons 4 and/or 6 produces four known products of undetermined significance. # Human basal ganglia The nature and distribution of PPT-1 has been studied in the human basal ganglia. The protein is expressed evenly throughout the caudate and putamen, and 80 to 85% of it exists in the beta-PPT isoform. 15-20% of the protein is in the gamma-PPT isoform, while no alpha-PPT was detected at all. # Species comparison In humans, beta-PPT is the dominant isoform in the brain, which contrasts with rats (predominantly gamma-PPT) and cows (alpha-PPT). While both human and rat PPT-1 produce substance P and neurokinin A, humans produce more neuropeptide K, whereas rats produce more neuropeptide gamma. In cow brains, PPT-1 primarily encodes substance P, but not other neurokinin A-derived peptides.

TAC1 Preprotachykinin-1, (abbreviated PPT-1, PPT-I, or PPT-A), is a precursor protein that in humans is encoded by the TAC1 gene.[1][2] # Isoforms and derivatives The protein has four isoforms—alpha-, beta-, gamma-, and delta-PPT—which can variably undergo post-translational modification to produce neurokinin A (formerly known as substance K) and substance P.[3][4] Alpha- and delta-PPT can only be modified to substance P, whereas beta- and gamma-PPT can produce both substance P and neurokinin A.[5] Neurokinin A can also be further modified to produce neuropeptide K (also known as neurokinin K) and neuropeptide gamma.[6] These hormones are thought to function as neurotransmitters which interact with nerve receptors and smooth muscle cells. They are known to induce behavioral responses and function as vasodilators and secretagogues. Alternative splicing of exons 4 and/or 6 produces four known products of undetermined significance.[2] # Human basal ganglia The nature and distribution of PPT-1 has been studied in the human basal ganglia. The protein is expressed evenly throughout the caudate and putamen, and 80 to 85% of it exists in the beta-PPT isoform. 15-20% of the protein is in the gamma-PPT isoform, while no alpha-PPT was detected at all.[4] # Species comparison In humans, beta-PPT is the dominant isoform in the brain, which contrasts with rats (predominantly gamma-PPT) and cows (alpha-PPT).[4] While both human and rat PPT-1 produce substance P and neurokinin A, humans produce more neuropeptide K, whereas rats produce more neuropeptide gamma. In cow brains, PPT-1 primarily encodes substance P, but not other neurokinin A-derived peptides.[4]

https://www.wikidoc.org/index.php/TAC1

182123bf33718210014ddcf12814a743a4b17fa0

wikidoc

TACT

TACT # Official Title Trial to Assess Chelation Therapy (TACT) # Objective The purpose of this study is to determine the safety and effectiveness of ethylene diamine tetra-acetic (EDTA) chelation therapy in individuals with coronary artery disease. # Sponsor Mt. Sinai Medical Center, Miami # Timeline The previous information was derived from ClinicalTrials.gov on 11/19/2013 using the identification number NCT00044213. # Study Description The previous information was derived from ClinicalTrials.gov on 11/19/2013 using the identification number NCT00044213. # Eligibility Criteria ## Inclusion Criteria - Heart attack at least 6 weeks prior to study start ## Exclusion Criteria - Serum creatinie level greater than 2.0 mg/dL - Platelet count less than 100,000/µL - Blood pressure greater than 160/100 - Chelation therapy within 5 years prior to study start - History of allergic reactions to EDTA or any of the therapy's components - Coronary or carotid revascularization procedures within 6 months prior to study start or a scheduled revascularization - Cigarette smoking within 3 months prior to study start - Childbearing potential - History of liver disease - Active heart failure or heart failure hospitalization within 6 months. - Diagnoses of additional medical conditions that could otherwise limit patient survival - Inability to tolerate 500-mL infusions weekly. # Outcomes ## Primary Outcomes A composite of total mortality, recurrent myocardial infarction, stroke, coronary revascularization, and hospitalization for angina. ## Secondary Outcomes A composite of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke. # Publications ## Stable Post-Myocardial Infarction Patients A follow up period of 55 months revealed a modest decrease in the adverse cardiovascular outcomes risks. In fact, 30% of post-MI patients who did not receive chelation therapy were reported to have the primary outcome compared to 26% of those who received the chelation therapy ( HR: 0.82; 95% CI: 0.69-0.99; p= 0.035). The association between chelation therapy and decrease in the risk of each of the components of the primary outcome was significant except for total mortality. Despite the moderate improvement in the cardiovascular outcomes, the findings of this study were not enough to promote chelation therapy as a treatment for stable post-myocardial infarct patients. ## Diabetic Post-Myocardial Infarction Patients The effect of chelation therapy on cardiovascular outcomes was investigated among diabetic patients enrolled in TACT. Among TACT enrolled patients, 633 patients had diabetes which was defined as self-reported diabetes, taking treatment for diabetes or having a fasting blood glucose superior to 126 mg/dL at enrollment. The use of chelation therapy infusions among post-myocardial infarction diabetic patients was associated with decrease in the primary endpoint. In fact, the primary end point occurred in 25 % of diabetic patients who were administered the chelation therapy compared to 38% in those who were not (HR, 0.59; 95% CI, 0.44–0.79; P<0.001). The effect of chelation therapy on the primary endpoint remained significant following adjustment for multiple subgroups (99.4% CI, 0.39–0.88; adjusted P=0.002). In addition, chelation therapy was associated with decreased all-cause mortality, an association that was no longer significant following adjustment for multiple subgroups.

TACT Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rim Halaby, M.D. [2] # Official Title Trial to Assess Chelation Therapy (TACT) # Objective The purpose of this study is to determine the safety and effectiveness of ethylene diamine tetra-acetic (EDTA) chelation therapy in individuals with coronary artery disease. # Sponsor Mt. Sinai Medical Center, Miami # Timeline The previous information was derived from ClinicalTrials.gov on 11/19/2013 using the identification number NCT00044213. # Study Description The previous information was derived from ClinicalTrials.gov on 11/19/2013 using the identification number NCT00044213. # Eligibility Criteria ## Inclusion Criteria - Heart attack at least 6 weeks prior to study start ## Exclusion Criteria - Serum creatinie level greater than 2.0 mg/dL - Platelet count less than 100,000/µL - Blood pressure greater than 160/100 - Chelation therapy within 5 years prior to study start - History of allergic reactions to EDTA or any of the therapy's components - Coronary or carotid revascularization procedures within 6 months prior to study start or a scheduled revascularization - Cigarette smoking within 3 months prior to study start - Childbearing potential - History of liver disease - Active heart failure or heart failure hospitalization within 6 months. - Diagnoses of additional medical conditions that could otherwise limit patient survival - Inability to tolerate 500-mL infusions weekly. # Outcomes ## Primary Outcomes A composite of total mortality, recurrent myocardial infarction, stroke, coronary revascularization, and hospitalization for angina. ## Secondary Outcomes A composite of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke. # Publications ## Stable Post-Myocardial Infarction Patients A follow up period of 55 months revealed a modest decrease in the adverse cardiovascular outcomes risks. In fact, 30% of post-MI patients who did not receive chelation therapy were reported to have the primary outcome compared to 26% of those who received the chelation therapy ( HR: 0.82; 95% CI: 0.69-0.99; p= 0.035). The association between chelation therapy and decrease in the risk of each of the components of the primary outcome was significant except for total mortality. Despite the moderate improvement in the cardiovascular outcomes, the findings of this study were not enough to promote chelation therapy as a treatment for stable post-myocardial infarct patients.[1] ## Diabetic Post-Myocardial Infarction Patients The effect of chelation therapy on cardiovascular outcomes was investigated among diabetic patients enrolled in TACT. Among TACT enrolled patients, 633 patients had diabetes which was defined as self-reported diabetes, taking treatment for diabetes or having a fasting blood glucose superior to 126 mg/dL at enrollment. The use of chelation therapy infusions among post-myocardial infarction diabetic patients was associated with decrease in the primary endpoint. In fact, the primary end point occurred in 25 % of diabetic patients who were administered the chelation therapy compared to 38% in those who were not (HR, 0.59; 95% CI, 0.44–0.79; P<0.001). The effect of chelation therapy on the primary endpoint remained significant following adjustment for multiple subgroups (99.4% CI, 0.39–0.88; adjusted P=0.002). In addition, chelation therapy was associated with decreased all-cause mortality, an association that was no longer significant following adjustment for multiple subgroups.[2]

https://www.wikidoc.org/index.php/TACT

625edd7827fbc3fa122b9662801a97e0015364d9

wikidoc

TAF1

TAF1 Transcription initiation factor TFIID subunit 1, also known as transcription initiation factor TFIID 250 kDa subunit (TAFII-250) or TBP-associated factor 250 kDa (p250), is a protein that in humans is encoded by the TAF1 gene. # Function Initiation of transcription by RNA polymerase II requires the activities of more than 70 polypeptides. The protein that coordinates these activities is the basal transcription factor TFIID, which binds to the core promoter to position the polymerase properly, serves as the scaffold for assembly of the remainder of the transcription complex, and acts as a channel for regulatory signals. TFIID is composed of the TATA-binding protein (TBP) and a group of evolutionarily conserved proteins known as TBP-associated factors or TAFs. TAFs may participate in basal transcription, serve as coactivators, function in promoter recognition or modify general transcription factors (GTFs) to facilitate complex assembly and transcription initiation. This gene encodes the largest subunit of TFIID. This subunit binds to core promoter sequences encompassing the transcription start site. It also binds to activators and other transcriptional regulators, and these interactions affect the rate of transcription initiation. This subunit contains two independent protein kinase domains at the N and C-terminals, but also possesses acetyltransferase activity and can act as a ubiquitin-activating/conjugating enzyme. Two transcripts encoding different isoforms have been identified for this gene. Histones are often acetylated to open DNA for transcription. TAF1 contains two bromodomains, which each can bind one of two acetyllysine residues at position 5 and 12 in the H4 tail, to stabilize the TBP-TATA box complex. # Clinical significance A mutation in TAF1 was identified that contributes to a phenotype with severe intellectual disability (ID), a characteristic intergluteal crease, and distinctive facial features, including a broad, upturned nose, sagging cheeks, downward sloping palpebral fissures, prominent periorbital ridges, deep-set eyes, relative hypertelorism, thin upper lip, a high-arched palate, prominent ears with thickened helices, and a pointed chin This is a non-synonymous change in TAF1 that results in an isoleucine (hydrophobic) to threonine (polar) change on the 1337th amino acid residue in the protein (NP_001273003.1). Two other mutations were reported in TAF1 in two families with intellectual disability, although further clinical details were not reported. # Interactions TAF1 has been shown to interact with: - CSNK2A1, - CCND1, - GTF2F1, - RB1, - TAF7, - TBP, and - UBTF.

TAF1 Transcription initiation factor TFIID subunit 1, also known as transcription initiation factor TFIID 250 kDa subunit (TAFII-250) or TBP-associated factor 250 kDa (p250), is a protein that in humans is encoded by the TAF1 gene.[1][2] # Function Initiation of transcription by RNA polymerase II requires the activities of more than 70 polypeptides. The protein that coordinates these activities is the basal transcription factor TFIID, which binds to the core promoter to position the polymerase properly, serves as the scaffold for assembly of the remainder of the transcription complex, and acts as a channel for regulatory signals. TFIID is composed of the TATA-binding protein (TBP) and a group of evolutionarily conserved proteins known as TBP-associated factors or TAFs. TAFs may participate in basal transcription, serve as coactivators, function in promoter recognition or modify general transcription factors (GTFs) to facilitate complex assembly and transcription initiation. This gene encodes the largest subunit of TFIID. This subunit binds to core promoter sequences encompassing the transcription start site. It also binds to activators and other transcriptional regulators, and these interactions affect the rate of transcription initiation. This subunit contains two independent protein kinase domains at the N and C-terminals, but also possesses acetyltransferase activity and can act as a ubiquitin-activating/conjugating enzyme. Two transcripts encoding different isoforms have been identified for this gene.[1] Histones are often acetylated to open DNA for transcription. TAF1 contains two bromodomains, which each can bind one of two acetyllysine residues at position 5 and 12 in the H4 tail, to stabilize the TBP-TATA box complex. # Clinical significance A mutation in TAF1 was identified that contributes to a phenotype with severe intellectual disability (ID), a characteristic intergluteal crease, and distinctive facial features, including a broad, upturned nose, sagging cheeks, downward sloping palpebral fissures, prominent periorbital ridges, deep-set eyes, relative hypertelorism, thin upper lip, a high-arched palate, prominent ears with thickened helices, and a pointed chin[3][4] This is a non-synonymous change in TAF1 that results in an isoleucine (hydrophobic) to threonine (polar) change on the 1337th amino acid residue in the protein (NP_001273003.1). Two other mutations were reported in TAF1 in two families with intellectual disability, although further clinical details were not reported.[5] # Interactions TAF1 has been shown to interact with: - CSNK2A1,[6] - CCND1,[7][8] - GTF2F1,[9][10][11][12] - RB1,[8][9][13][14] - TAF7,[15] - TBP,[9][16][17][18] and - UBTF.[19]

https://www.wikidoc.org/index.php/TAF1

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wikidoc

TAF4

TAF4 Transcription initiation factor TFIID subunit 4 is a protein that in humans is encoded by the TAF4 gene. # Function Initiation of transcription by RNA polymerase II requires the activities of more than 70 polypeptides. The protein that coordinates these activities is transcription factor IID (TFIID), which binds to the core promoter to position the polymerase properly, serves as the scaffold for assembly of the remainder of the transcription complex, and acts as a channel for regulatory signals. TFIID is composed of the TATA-binding protein (TBP) and a group of evolutionarily conserved proteins known as TBP-associated factors or TAFs. TAFs may participate in basal transcription, serve as coactivators, function in promoter recognition or modify general transcription factors (GTFs) to facilitate complex assembly and transcription initiation. This gene encodes one of the larger subunits of TFIID that has been shown to potentiate transcriptional activation by retinoic acid, thyroid hormone and vitamin D3 receptors. In addition, this subunit interacts with the transcription factor CREB, which has a glutamine-rich activation domain, and binds to other proteins containing glutamine-rich regions. Aberrant binding to this subunit by proteins with expanded polyglutamine regions has been suggested as one of the pathogenetic mechanisms underlying a group of neurodegenerative disorders referred to as polyglutamine diseases. # Interactions TAF4 has been shown to interact with: - CBX5m - TATA binding protein, and - Transcription initiation protein SPT3 homolog. # Protein domain Yeast TFIID comprises the TATA binding protein and 14 TBP-associated factors (TAFIIs), nine of which contain histone-fold domains (INTERPRO). The C-terminal region of the TFIID-specific yeast TAF4 (yTAF4) containing the HFD shares strong sequence similarity with Drosophila (d)TAF4 and human TAF4. A structure/function analysis of yTAF4 demonstrates that the HFD, a short conserved C-terminal domain (CCTD), and the region separating them are all required for yTAF4 function. This region of similarity is found in Transcription initiation factor TFIID component TAF4.

TAF4 Transcription initiation factor TFIID subunit 4 is a protein that in humans is encoded by the TAF4 gene.[1][2][3] # Function Initiation of transcription by RNA polymerase II requires the activities of more than 70 polypeptides. The protein that coordinates these activities is transcription factor IID (TFIID), which binds to the core promoter to position the polymerase properly, serves as the scaffold for assembly of the remainder of the transcription complex, and acts as a channel for regulatory signals. TFIID is composed of the TATA-binding protein (TBP) and a group of evolutionarily conserved proteins known as TBP-associated factors or TAFs. TAFs may participate in basal transcription, serve as coactivators, function in promoter recognition or modify general transcription factors (GTFs) to facilitate complex assembly and transcription initiation. This gene encodes one of the larger subunits of TFIID that has been shown to potentiate transcriptional activation by retinoic acid, thyroid hormone and vitamin D3 receptors. In addition, this subunit interacts with the transcription factor CREB, which has a glutamine-rich activation domain, and binds to other proteins containing glutamine-rich regions. Aberrant binding to this subunit by proteins with expanded polyglutamine regions has been suggested as one of the pathogenetic mechanisms underlying a group of neurodegenerative disorders referred to as polyglutamine diseases.[3] # Interactions TAF4 has been shown to interact with: - CBX5m[4] - TATA binding protein,[5][6] and - Transcription initiation protein SPT3 homolog.[7] # Protein domain Yeast TFIID comprises the TATA binding protein and 14 TBP-associated factors (TAFIIs), nine of which contain histone-fold domains (INTERPRO). The C-terminal region of the TFIID-specific yeast TAF4 (yTAF4) containing the HFD shares strong sequence similarity with Drosophila (d)TAF4 and human TAF4. A structure/function analysis of yTAF4 demonstrates that the HFD, a short conserved C-terminal domain (CCTD), and the region separating them are all required for yTAF4 function. This region of similarity is found in Transcription initiation factor TFIID component TAF4.[8]

https://www.wikidoc.org/index.php/TAF4

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wikidoc

TAF7

TAF7 Transcription initiation factor TFIID subunit 7 also known as TAFII55 is a protein that in humans is encoded by the TAF7 gene. # Function The intronless gene for this transcription coactivator is located between the protocadherin beta and gamma gene clusters on chromosome 5. The protein encoded by this gene is a component of the TFIID protein complex, a complex which binds to the TATA box in class II promoters and recruits RNA polymerase II and other factors. This particular subunit interacts with the largest TFIID subunit, as well as multiple transcription activators. The protein is required for transcription by promoters targeted by RNA polymerase II. The general transcription factor, TFIID, consists of the TATA-binding protein (TBP) associated with a series of TBP-associated factors (TAFs) that together participate in the assembly of the transcription preinitiation complex. TAFII55 binds to TAFII250 and inhibits its acetyltransferase activity. The exact role of TAFII55 is currently unknown but studies have shown that it interacts with the C-jun pathway. The conserved region is situated towards the N-terminal of the protein. This entry talks about the N-terminal domain. Crystallographic studies have revealed a very significant hydrophobic pocket between TAF7 and TAF1, its main binding partner. Due to the incredible hydrophobicity of this interaction, its unlikely that TAF1 would be able to fold properly without the presence of TAF7. Thus, it is possible that TAF7 is required for proper production of TAF1 # Interactions TAF7 has been shown to interact with: - TAF15, - TAF1, and - TATA binding protein.

TAF7 Transcription initiation factor TFIID subunit 7 also known as TAFII55 is a protein that in humans is encoded by the TAF7 gene.[1] # Function The intronless gene for this transcription coactivator is located between the protocadherin beta and gamma gene clusters on chromosome 5. The protein encoded by this gene is a component of the TFIID protein complex, a complex which binds to the TATA box in class II promoters and recruits RNA polymerase II and other factors. This particular subunit interacts with the largest TFIID subunit, as well as multiple transcription activators. The protein is required for transcription by promoters targeted by RNA polymerase II.[2] The general transcription factor, TFIID, consists of the TATA-binding protein (TBP) associated with a series of TBP-associated factors (TAFs) that together participate in the assembly of the transcription preinitiation complex. TAFII55 binds to TAFII250 and inhibits its acetyltransferase activity. The exact role of TAFII55 is currently unknown but studies have shown that it interacts with the C-jun pathway.[3] The conserved region is situated towards the N-terminal of the protein.[4] This entry talks about the N-terminal domain. Crystallographic studies have revealed a very significant hydrophobic pocket between TAF7 and TAF1, its main binding partner. Due to the incredible hydrophobicity of this interaction, its unlikely that TAF1 would be able to fold properly without the presence of TAF7. Thus, it is possible that TAF7 is required for proper production of TAF1[5] # Interactions TAF7 has been shown to interact with: - TAF15,[6] - TAF1,[4] and - TATA binding protein.[7][8]

https://www.wikidoc.org/index.php/TAF7

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wikidoc

TAF9

TAF9 TAF9 RNA polymerase II, TATA box binding protein (TBP)-associated factor, 32kDa, also known as TAF9, is a protein that in humans is encoded by the TAF9 gene. # Function Initiation of transcription by RNA polymerase II requires the activities of more than 70 polypeptides. The protein complex that coordinates these activities is transcription factor IID (TFIID), which binds to the core promoter to position the polymerase properly, serves as the scaffold for assembly of the remainder of the transcription complex, and acts as a channel for regulatory signals. TFIID is composed of the TATA-binding protein (TBP) and a group of evolutionarily conserved proteins known as TBP-associated factors or TAFs. TAFs may participate in basal transcription, serve as coactivators, function in promoter recognition or modify general transcription factors (GTFs) to facilitate complex assembly and transcription initiation. This gene encodes one of the smaller subunits of TFIID that binds to the basal transcription factor GTF2B as well as to several transcriptional activators such as p53 and VP16. A similar but distinct gene (TAF9B) has been found on the X chromosome and a pseudogene has been identified on chromosome 19. Alternative splicing results in multiple transcript variants encoding different isoforms. # Structure The 17-amino-acid-long trans-activating domains (TAD) of several transcription factors were reported to bind directly to TAF9: p53, VP16, HSF1, NF-IL6, NFAT1, NF-κB, and ALL1/MLL1. Inside of these 17 amino acids, a unique Nine-amino-acid transactivation domain (9aaTAD) was identified for each reported transcription factor. 9aaTAD is a novel domain common to a large superfamily of eukaryotic transcription factors represented by Gal4, Oaf1, Leu3, Rtg3, Pho4, Gln4, Gcn4 in yeast and by p53, NFAT, NF-κB and VP16 in mammals. TAF9 is supposed to be a universal transactivation cofactor for 9aaTAD transcription factors. # Interactions TAF9 has been shown to interact with: - GCN5L2, - Myc, - SF3B3, - SUPT7L, - TADA3L, - TAF5, - TAF6L, - TAF10, - TAF12, - TAF5L, - TATA binding protein, - Transcription initiation protein SPT3 homolog, and - Transformation/transcription domain-associated protein.

TAF9 TAF9 RNA polymerase II, TATA box binding protein (TBP)-associated factor, 32kDa, also known as TAF9, is a protein that in humans is encoded by the TAF9 gene.[1][2] # Function Initiation of transcription by RNA polymerase II requires the activities of more than 70 polypeptides. The protein complex that coordinates these activities is transcription factor IID (TFIID), which binds to the core promoter to position the polymerase properly, serves as the scaffold for assembly of the remainder of the transcription complex, and acts as a channel for regulatory signals. TFIID is composed of the TATA-binding protein (TBP) and a group of evolutionarily conserved proteins known as TBP-associated factors or TAFs. TAFs may participate in basal transcription, serve as coactivators, function in promoter recognition or modify general transcription factors (GTFs) to facilitate complex assembly and transcription initiation. This gene encodes one of the smaller subunits of TFIID that binds to the basal transcription factor GTF2B as well as to several transcriptional activators such as p53 and VP16. A similar but distinct gene (TAF9B) has been found on the X chromosome and a pseudogene has been identified on chromosome 19. Alternative splicing results in multiple transcript variants encoding different isoforms.[1] # Structure The 17-amino-acid-long trans-activating domains (TAD) of several transcription factors were reported to bind directly to TAF9: p53, VP16, HSF1, NF-IL6, NFAT1, NF-κB, and ALL1/MLL1.[3] Inside of these 17 amino acids, a unique Nine-amino-acid transactivation domain (9aaTAD) was identified for each reported transcription factor.[4] 9aaTAD is a novel domain common to a large superfamily of eukaryotic transcription factors represented by Gal4, Oaf1, Leu3, Rtg3, Pho4, Gln4, Gcn4 in yeast and by p53, NFAT, NF-κB and VP16 in mammals.[5] TAF9 is supposed to be a universal transactivation cofactor for 9aaTAD transcription factors.[4] # Interactions TAF9 has been shown to interact with: - GCN5L2,[6] - Myc,[7] - SF3B3,[6] - SUPT7L,[6] - TADA3L,[6] - TAF5,[6][8] - TAF6L,[6] - TAF10,[6] - TAF12,[6] - TAF5L,[6] - TATA binding protein,[6][9] - Transcription initiation protein SPT3 homolog,[6] and - Transformation/transcription domain-associated protein.[6]

https://www.wikidoc.org/index.php/TAF9

c032c9bc4edc39ac35cc4069dea49dbb9a4ac21c

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TAL2

TAL2 T-cell acute lymphocytic leukemia 2, also known as TAL2, is a protein which in humans is encoded by the TAL2 gene. # Function TAL2 is a member of the basic helix-loop-helix family of transcription factors. # Clinical significance Tumor-specific alterations of the TAL2 gene occurs in some patients with T-cell acute lymphoblastic leukemia (T-ALL).

TAL2 T-cell acute lymphocytic leukemia 2, also known as TAL2, is a protein which in humans is encoded by the TAL2 gene.[1][2] # Function TAL2 is a member of the basic helix-loop-helix family of transcription factors.[3] # Clinical significance Tumor-specific alterations of the TAL2 gene occurs in some patients with T-cell acute lymphoblastic leukemia (T-ALL).[2][4]

https://www.wikidoc.org/index.php/TAL2

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wikidoc

TBCE

TBCE Tubulin-specific chaperone E is a protein that in humans is encoded by the TBCE gene. Cofactor E is one of four proteins (cofactors A, D, E, and C) involved in the pathway leading to correctly folded beta-tubulin from folding intermediates. Cofactors A and D are believed to play a role in capturing and stabilizing beta-tubulin intermediates in a quasi-native confirmation. Cofactor E binds to the cofactor D/beta-tubulin complex; interaction with cofactor C then causes the release of beta-tubulin polypeptides that are committed to the native state. Two transcript variants encoding the same protein have been found for this gene. The TBCE gene is either deleted or mutated in Sanjad-Sakati Syndrome

TBCE Tubulin-specific chaperone E is a protein that in humans is encoded by the TBCE gene.[1][2] Cofactor E is one of four proteins (cofactors A, D, E, and C) involved in the pathway leading to correctly folded beta-tubulin from folding intermediates. Cofactors A and D are believed to play a role in capturing and stabilizing beta-tubulin intermediates in a quasi-native confirmation. Cofactor E binds to the cofactor D/beta-tubulin complex; interaction with cofactor C then causes the release of beta-tubulin polypeptides that are committed to the native state. Two transcript variants encoding the same protein have been found for this gene.[2] The TBCE gene is either deleted or mutated in Sanjad-Sakati Syndrome

https://www.wikidoc.org/index.php/TBCE

b5a48b04f2adce89bd52a6d6575a9bcafffe7d13

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TBR1

TBR1 T-box, brain, 1 is a transcription factor protein important in vertebrate embryo development. It is encoded by the TBR1 gene. This gene is also known by several other names: T-Brain 1, TBR-1, TES-56, and MGC141978. TBR1 is a member of the TBR1 subfamily of T-box family transcription factors, which share a common DNA-binding domain. Other members of the TBR1 subfamily include EOMES and TBX21. TBR1 is involved in the differentiation and migration of neurons and is required for normal brain development. TBR1 interacts with various genes and proteins in order to regulate cortical development, specifically within layer VI of the developing six-layered human cortex. Studies show that TBR1 may play a role in major neurological diseases such as Alzheimer's Disease (AD) and Parkinson's Disease (PD). # Discovery TBR1 was identified in 1995 by the Nina Ireland Laboratory of Developmental Neurobiology Center at the University of California, San Francisco. The gene, initially named TES-56, was found to be largely expressed in the telencephalic vesicles of the developing forebrain of mice. The protein product of TES-56 was discovered to be homologous to the Brachyury protein, a T-box transcription factor, which plays a role in establishing symmetry during embryonic development. Thus, due to its relation to T-box genes (such as Tbx-1, Tbx-2, Tbx-3), TES-56 was renamed TBR1. # Human TBR1 gene and encoded protein The human TBR1 gene is located on the q arm of the positive strand of chromosome 2. It is 8,954 base pairs in length. TBR1 is one of the three genes that make up the TBR1 subfamily of T-box genes. The two other genes that form the TBR1 subfamily are EOMES (also known as TBR2) and TBX21 (also known as T-BET). TBR1 is also known as T-box Brain Protein, T-Brain 1, and TES-56. The encoded protein consists of 682 amino acid residues and has a predicted molecular weight of 74,053 Da. It is composed of 6 exons. # Functions Tbr1 is a protein, called a transcription factor, that binds to DNA and regulates the transcription of genes into mRNA. It is expressed in postmitotic projection neurons and is critical for normal brain development. Tbr1 has been shown to be expressed in the developing olfactory bulb. Tbr1 has also been observed in the developing cerebral cortex. Tbr1 has several functions. These include involvement in the developmental process, brain development, neuronal differentiation, axon guidance, and regulation of neurons in the developing neocortex. ## Neuronal differentiation Tbr1, along with Pax6 and Tbr2, has a role in glutamatergic projection neuron differentiation. Glutamatergic neurons make and release in an activity-dependent manner the excitatory neurotransmitter glutamate as opposed to the inhibitory neurotransmitter GABA. The transition from radial glial cells to postmitotic projection neurons occurs in three steps, each associated with one of the aforementioned transcription factors. The first starts out with the expression of Pax6 in radial glial cells found primarily at the ventricular surface. In the next step, Pax6 is downregulated and Tbr2 is expressed as the cell differentiates into an intermediate progenitor cell. Likewise, in the final step, Tbr2 is extremely downregulated to undetectable levels as Tbr1 signals the transition into a postmitotic projection neuron. ## Modulation of NMDAR In cultured hippocampal neurons, Tbr1 and calcium/calmodulin-dependent serine kinase (CASK) interact with CASK-interacting nucleosome assembly protein (CINAP) to modulate the expression of N-methyl-D-aspartic acid receptor subunit 2b (NR2b) by acting on its promoter region. Tbr1 is a transcriptional regulator of NR1, an essential subunit of NMDA receptors. ## Axon guidance Cells that stop dividing (post-mitotic) and differentiate into neurons early in cortical development are important in laying the groundwork on which other developing neurons can be guided to their proper destination. Tbr1 aids in neuronal migration in the early development of the cerebral cortex. It is largely expressed in post-mitotic neurons of the preplate, which forms a foundation upon which neurons are able to grow and move. As a transcription factor, Tbr1 modulates the expression of RELN, which encodes the Reln protein that forms part of the extracellular matrix of cells. Thus, through regulation of Reln expression, Tbr1 regulates the formation of the matrix through which neurons migrate. Without Tbr1, neurons fail to migrate properly. # Tissue and cellular distribution Being a transcription factor, a protein that binds to specific DNA sites and thereby regulates the activity of specific genes, Tbr1 is localized in the nucleus where the cell’s DNA is located. Tbr1 is expressed in glutamergic neurons rather than GABAergic neurons. Tbr1 is expressed mainly in early-born postmitotic neurons of the developing cerebral cortex—in particular, the preplate and layer VI neurons. The preplate forms the architectural network of neurons that help developing neurons migrate. Successive migrations of neurons divide the preplate such that its inner cells form the cortical plate while its outer cells form the marginal zone. The cortical plate and the marginal zone eventually develop into six cortical layers, known as the neocortex, present in the mature cerebral cortex. These layers are numbered I-VI with layer VI being the deepest and forming first, while the remaining layers grow outward from it (from V to I). Layers II-VI develop from the cortical plate and layer I forms from the marginal zone. The subplate, intermediate zone, subventricular zone, and ventricular zone are found progressively deeper to these developing cortical layers. High expression of Tbr1 is seen in the marginal zone, cortical plate, and subplate of the developing cortex whereas little expression is seen in the subventricular zone. No Tbr1 expression has been observed in the ventricular zone. Other regions of Tbr1 expression are: the olfactory bulbs and olfactory nuclei, the lateral hypothalamus region, the entopeduncular nucleus, the eminentia thalami. # Non-human orthologs Orthologs of the human TBR1 gene have been identified in chimpanzee, dog, cow, rat, mouse, and zebrafish. ## Mice In mice, TBR1 has been found to function in development of the brain, eye, immune system, mesoderm, and placenta. It is also involved in glutamatergic neuronal differentiation in the developing mouse brain. It was discovered that Tbr-1 is expressed by postmitotic cortical neurons in mice and in humans. One target gene of TBR1 in the mouse brain is RELN or Reelin. Tbr-1 mutant mice have been found to have reduced RELN expression, resulting in improper neuronal migration, particularly in Cajal-Retzius cells of the marginal zone. Other studies in mice have found that TBR1 is a repressor or Fezf2. It has also been found to negatively regulate corticospinal tract formation. ## Zebrafish Studies in the zebrafish Danio rerio show that TBR1 is highly conserved across species. TBR1 cDNA clones from zebrafish were acquired by screening a zebrafish embryo using a phosphorus labeled probe. The TBR1 found in zebrafish (zf-TBR1) has 83-97% amino acid identity to orthologs in humans (hu-TBR1), xenopus (x-EOMES), and mice (mu-TBR1). The zebrafish TBR1 is only expressed in the forebrain, not in other regions of the zebrafish embryo. ## Lancelets The evolution of TBR1 has been studied in amphioxi, also known as lancelets. A T-box-containing cDNA was isolated in the lancelet Branchiostoma belcheri and found to possess a T-domain orthologous to that of the T-Brain subfamily of T-box genes, specifically TBR1. However, lancelets lack a true brain and no TBR1 transcripts were found in the neural tissue of the lancelet. This suggests that the neuronal role of TBR1 evolved in vertebrates after the lancelet lineage had already diverged from that of vertebrates. # Gene regulation TBR1 both positively and negatively regulates gene expression in postmitotic neurons. ## Genes regulated by TBR1 Fezf2 is a gene that is regulated by TBR1. Fezf2 expression is observed in layer V of the cerebral cortex. The cerebral cortex is constructed in six layers. Fezf2 expression is restricted to layer V for proper development and migration of neurons of the corticospinal tract, which is derived from layer V neurons and is involved in voluntary muscular control. Recent studies show that TBR1, expressed in layer VI, binds directly to the Fezf2 gene, preventing Fezf2 expression in layer VI. In this manner, TBR1 acts as a transcription repressor of Fezf2. Mutation of TBR1 results in Fezf2 expression in layer VI and malformation of the corticospinal tract. Abnormal activation of TBR1 in layer V eliminates corticospinal tract formation. Bhlhb5 is a gene marker in the mouse brain, which is involved in differentiation of caudal identity in layer V neurons of the developing cortex, and is regulated by TBR1. It is expressed at high levels in caudal regions, but is not generally observed in the frontal cortex. Tbr1 is expressed at very high levels in the frontal cortex and very lower levels in the caudal regions. Using tbr1 null mutants, it was found that Bhlhb5 is up-regulated in the absence of TBR1. This up-regulation of Bhlhb5 led to the conclusion that tbr1 suppresses caudal identity while promoting frontal identity. The gene Auts2 is also regulated by TBR1. The autism susceptibility candidate 2 gene (Auts2) is a marker of frontal identity in the developing cortex and has been linked to mental retardation and autism. Auts2 is a target of the transcription factor, TBR1, in the neocortex. TBR1 is involved in both the binding and activation of the Auts2 gene. ## Co-regulatory proteins Tbr1 forms a complex with CASK and regulates gene expression in cortical development. Tbr1 binds to the guanylate kinase (GK) domain of CASK. It was determined that the C-terminal domain of Tbr1 in crucial and solely capable of this process. Through luciferase reporter assays of neurons in the hippocampus, it was found that increased Tbr1/CASK complex expression results in enhanced promoter activity in genes downstream of TBR1 such as NMDAR subunit 2b (NMDAR2b), glycine transporter, interleukin-7 receptor (IL-7R) and OX-2 genes. NMDAR2b experienced the greatest change in activity. Tbr1 and CASK also play an important role in activation of the RELN gene. One study suggests that CASK acts as a coactivator of TBR1, interacting with CINAP (CASK-interacting nucleosome assembly protein) to form a complex with Tbr1. The Tbr1/CASK/CINAP complex regulates expression of NMDAR2b and RELN, which both play important roles in long-term potentiation. Sox5 is another co-regulatory protein of Tbr1. Sox5 is a marker of layer VI neurons in the neocortex. It aids in the suppression of layer V neuron identity within layer VI cortical neurons through suppression of Fezf2. TBR1 is involved in the downstream regulation of Sox5. Sox5 expression was reduced in Tbr1 null mutants. It has been found that Sox5 interacts with Tbr1 to regulate Fezf2 transcription in layer VI cortical neurons. ## Transcription factors that regulate the expression of Tbr1 Studies suggest that the Af9 protein acts as a repressor of Tbr1 in the upper layers of the six-layer developing cerebral cortex, thereby confining Tbr1 to the lower cortical layers (preplate, subplate, layer VI). This process is regulated through interaction of Af9 with the methyltransferase DOT1L, which methylates histone H3 lysine 79 (H3K79). Af9 association with DOT1L enhances methylation of H3K79 at the TBR1 transcription start site, thereby interfering with RNA polymerase II (RNAPolII) activity and reducing TBR1 expression. Mutants of Af9 experience increased dimethylation of H3K79 and increased TBR1 expression. # Clinical significance TBR1 has been implicated in alterations in the brain that may lead to Alzheimer's Disease (AD) and Parkinson's Disease (PD). TBR1 expressing mice showed that cholinergic neurons of the basal forebrain (ChBF), the degeneration of which are involved in the development of AD and PD, migrate from the ventral pallium to the subpallium. This was confirmed using TBR1 null mice. In the future, the researchers plan to explore the role of amyloid precursor protein (APP) in neuronal migration and linkage to these diseases. Reduced function of NMDA receptors play a role in schizophrenia. This diminished function of NMDA receptor may be correlated with the reduced expression of the NMDA receptor 2B subunit (NR2b), which has also been linked to schizophrenia. TBR1, in complex with the protein, CINAP, is responsible for regulating transcription of the NR2b gene. It was hypothesized in one 2010 study that reduced TBR1 and CINAP expression may be responsible for the reduced expression of the NR2b subunit observed in brains of postmortem schizophrenics. However, TBR1 and CINAP expression were not significantly reduced in the postmortem brains, suggesting that synthesis and processing of NR2b via TBR1 is not responsible for reduced NR2b expression in schizophrenics. TBR1 expression has been shown to be downregulated by embryonic exposure to cocaine. Prenatal cocaine exposure in a mouse model caused a decrease in both GABA neuron migration from the basal to the dorsal forebrain and radial neuron migration in the dorsal forebrain. This exposure also decreased TBR1 and TBR2 expression. However, further research showed that cocaine exposure only delayed TBR1 expression and did not cause permanent downregulation. Therefore, in models of prenatal cocaine exposure both migration and maturation of these progenitor cells is delayed. TBR1 is also used in immunohistochemical techniques in neurological research. It has been used to identify layer VI developing cortical neurons as well as the prethalamic eminence, pallium, and dorsal forebrain. The presence of TBR1 in stem cells responding to telencephalon injury implicates the normal function of these cells in this region of the brain. Mutations of this gene have also been associated with medulloblastoma.

TBR1 T-box, brain, 1 is a transcription factor protein important in vertebrate embryo development. It is encoded by the TBR1 gene.[1][2] This gene is also known by several other names: T-Brain 1, TBR-1, TES-56, and MGC141978.[1] TBR1 is a member of the TBR1 subfamily of T-box family transcription factors, which share a common DNA-binding domain. Other members of the TBR1 subfamily include EOMES and TBX21. TBR1 is involved in the differentiation and migration of neurons and is required for normal brain development. TBR1 interacts with various genes and proteins in order to regulate cortical development, specifically within layer VI of the developing six-layered human cortex.[3] Studies show that TBR1 may play a role in major neurological diseases such as Alzheimer's Disease (AD) and Parkinson's Disease (PD). # Discovery TBR1 was identified in 1995 by the Nina Ireland Laboratory of Developmental Neurobiology Center at the University of California, San Francisco. The gene, initially named TES-56, was found to be largely expressed in the telencephalic vesicles of the developing forebrain of mice. The protein product of TES-56 was discovered to be homologous to the Brachyury protein, a T-box transcription factor, which plays a role in establishing symmetry during embryonic development. Thus, due to its relation to T-box genes (such as Tbx-1, Tbx-2, Tbx-3), TES-56 was renamed TBR1.[2] # Human TBR1 gene and encoded protein The human TBR1 gene is located on the q arm of the positive strand of chromosome 2. It is 8,954 base pairs in length.[1] TBR1 is one of the three genes that make up the TBR1 subfamily of T-box genes. The two other genes that form the TBR1 subfamily are EOMES (also known as TBR2) and TBX21 (also known as T-BET). TBR1 is also known as T-box Brain Protein, T-Brain 1, and TES-56.[2] The encoded protein consists of 682 amino acid residues and has a predicted molecular weight of 74,053 Da. It is composed of 6 exons.[1] # Functions Tbr1 is a protein, called a transcription factor, that binds to DNA and regulates the transcription of genes into mRNA. It is expressed in postmitotic projection neurons and is critical for normal brain development. Tbr1 has been shown to be expressed in the developing olfactory bulb. Tbr1 has also been observed in the developing cerebral cortex.[2] Tbr1 has several functions. These include involvement in the developmental process, brain development, neuronal differentiation, axon guidance, and regulation of neurons in the developing neocortex. ## Neuronal differentiation Tbr1, along with Pax6 and Tbr2, has a role in glutamatergic projection neuron differentiation. Glutamatergic neurons make and release in an activity-dependent manner the excitatory neurotransmitter glutamate as opposed to the inhibitory neurotransmitter GABA.[4] The transition from radial glial cells to postmitotic projection neurons occurs in three steps, each associated with one of the aforementioned transcription factors. The first starts out with the expression of Pax6 in radial glial cells found primarily at the ventricular surface. In the next step, Pax6 is downregulated and Tbr2 is expressed as the cell differentiates into an intermediate progenitor cell. Likewise, in the final step, Tbr2 is extremely downregulated to undetectable levels as Tbr1 signals the transition into a postmitotic projection neuron.[5] ## Modulation of NMDAR In cultured hippocampal neurons, Tbr1 and calcium/calmodulin-dependent serine kinase (CASK) interact with CASK-interacting nucleosome assembly protein (CINAP) to modulate the expression of N-methyl-D-aspartic acid receptor subunit 2b (NR2b) by acting on its promoter region.[6] Tbr1 is a transcriptional regulator of NR1, an essential subunit of NMDA receptors.[7] ## Axon guidance Cells that stop dividing (post-mitotic) and differentiate into neurons early in cortical development are important in laying the groundwork on which other developing neurons can be guided to their proper destination. Tbr1 aids in neuronal migration in the early development of the cerebral cortex. It is largely expressed in post-mitotic neurons of the preplate, which forms a foundation upon which neurons are able to grow and move. As a transcription factor, Tbr1 modulates the expression of RELN, which encodes the Reln protein that forms part of the extracellular matrix of cells. Thus, through regulation of Reln expression, Tbr1 regulates the formation of the matrix through which neurons migrate. Without Tbr1, neurons fail to migrate properly.[4] # Tissue and cellular distribution Being a transcription factor, a protein that binds to specific DNA sites and thereby regulates the activity of specific genes, Tbr1 is localized in the nucleus where the cell’s DNA is located. Tbr1 is expressed in glutamergic neurons rather than GABAergic neurons.[4] Tbr1 is expressed mainly in early-born postmitotic neurons of the developing cerebral cortex—in particular, the preplate and layer VI neurons. The preplate forms the architectural network of neurons that help developing neurons migrate. Successive migrations of neurons divide the preplate such that its inner cells form the cortical plate while its outer cells form the marginal zone. The cortical plate and the marginal zone eventually develop into six cortical layers, known as the neocortex, present in the mature cerebral cortex. These layers are numbered I-VI with layer VI being the deepest and forming first, while the remaining layers grow outward from it (from V to I). Layers II-VI develop from the cortical plate and layer I forms from the marginal zone. The subplate, intermediate zone, subventricular zone, and ventricular zone are found progressively deeper to these developing cortical layers. High expression of Tbr1 is seen in the marginal zone, cortical plate, and subplate of the developing cortex whereas little expression is seen in the subventricular zone.[4] No Tbr1 expression has been observed in the ventricular zone.[4] Other regions of Tbr1 expression are: the olfactory bulbs and olfactory nuclei, the lateral hypothalamus region, the entopeduncular nucleus, the eminentia thalami.[4] # Non-human orthologs Orthologs of the human TBR1 gene have been identified in chimpanzee, dog, cow, rat, mouse, and zebrafish. ## Mice In mice, TBR1 has been found to function in development of the brain, eye, immune system, mesoderm, and placenta. It is also involved in glutamatergic neuronal differentiation in the developing mouse brain. It was discovered that Tbr-1 is expressed by postmitotic cortical neurons in mice and in humans. One target gene of TBR1 in the mouse brain is RELN or Reelin. Tbr-1 mutant mice have been found to have reduced RELN expression, resulting in improper neuronal migration, particularly in Cajal-Retzius cells of the marginal zone.[8] Other studies in mice have found that TBR1 is a repressor or Fezf2. It has also been found to negatively regulate corticospinal tract formation.[9] ## Zebrafish Studies in the zebrafish Danio rerio show that TBR1 is highly conserved across species. TBR1 cDNA clones from zebrafish were acquired by screening a zebrafish embryo using a phosphorus labeled probe. The TBR1 found in zebrafish (zf-TBR1) has 83-97% amino acid identity to orthologs in humans (hu-TBR1), xenopus (x-EOMES), and mice (mu-TBR1). The zebrafish TBR1 is only expressed in the forebrain, not in other regions of the zebrafish embryo.[10] ## Lancelets The evolution of TBR1 has been studied in amphioxi, also known as lancelets. A T-box-containing cDNA was isolated in the lancelet Branchiostoma belcheri and found to possess a T-domain orthologous to that of the T-Brain subfamily of T-box genes, specifically TBR1.[11] However, lancelets lack a true brain and no TBR1 transcripts were found in the neural tissue of the lancelet.[11] This suggests that the neuronal role of TBR1 evolved in vertebrates after the lancelet lineage had already diverged from that of vertebrates.[2][11] # Gene regulation TBR1 both positively and negatively regulates gene expression in postmitotic neurons.[12] ## Genes regulated by TBR1 Fezf2 is a gene that is regulated by TBR1. Fezf2 expression is observed in layer V of the cerebral cortex. The cerebral cortex is constructed in six layers. Fezf2 expression is restricted to layer V for proper development and migration of neurons of the corticospinal tract, which is derived from layer V neurons and is involved in voluntary muscular control. Recent studies show that TBR1, expressed in layer VI, binds directly to the Fezf2 gene, preventing Fezf2 expression in layer VI. In this manner, TBR1 acts as a transcription repressor of Fezf2.[9] Mutation of TBR1 results in Fezf2 expression in layer VI and malformation of the corticospinal tract. Abnormal activation of TBR1 in layer V eliminates corticospinal tract formation.[9] Bhlhb5 is a gene marker in the mouse brain, which is involved in differentiation of caudal identity in layer V neurons of the developing cortex, and is regulated by TBR1. It is expressed at high levels in caudal regions, but is not generally observed in the frontal cortex. Tbr1 is expressed at very high levels in the frontal cortex and very lower levels in the caudal regions. Using tbr1 null mutants, it was found that Bhlhb5 is up-regulated in the absence of TBR1. This up-regulation of Bhlhb5 led to the conclusion that tbr1 suppresses caudal identity while promoting frontal identity.[12] The gene Auts2 is also regulated by TBR1. The autism susceptibility candidate 2 gene (Auts2) is a marker of frontal identity in the developing cortex and has been linked to mental retardation and autism.[13][14] Auts2 is a target of the transcription factor, TBR1, in the neocortex.[12] TBR1 is involved in both the binding and activation of the Auts2 gene.[12] ## Co-regulatory proteins Tbr1 forms a complex with CASK and regulates gene expression in cortical development. Tbr1 binds to the guanylate kinase (GK) domain of CASK. It was determined that the C-terminal domain of Tbr1 in crucial and solely capable of this process.[3] Through luciferase reporter assays of neurons in the hippocampus, it was found that increased Tbr1/CASK complex expression results in enhanced promoter activity in genes downstream of TBR1 such as NMDAR subunit 2b (NMDAR2b), glycine transporter, interleukin-7 receptor (IL-7R) and OX-2 genes. NMDAR2b experienced the greatest change in activity.[7] Tbr1 and CASK also play an important role in activation of the RELN gene. One study suggests that CASK acts as a coactivator of TBR1, interacting with CINAP (CASK-interacting nucleosome assembly protein) to form a complex with Tbr1. The Tbr1/CASK/CINAP complex regulates expression of NMDAR2b and RELN, which both play important roles in long-term potentiation.[15] Sox5 is another co-regulatory protein of Tbr1. Sox5 is a marker of layer VI neurons in the neocortex. It aids in the suppression of layer V neuron identity within layer VI cortical neurons through suppression of Fezf2. TBR1 is involved in the downstream regulation of Sox5. Sox5 expression was reduced in Tbr1 null mutants.[12] It has been found that Sox5 interacts with Tbr1 to regulate Fezf2 transcription in layer VI cortical neurons.[9][12] ## Transcription factors that regulate the expression of Tbr1 Studies suggest that the Af9 protein acts as a repressor of Tbr1 in the upper layers of the six-layer developing cerebral cortex, thereby confining Tbr1 to the lower cortical layers (preplate, subplate, layer VI). This process is regulated through interaction of Af9 with the methyltransferase DOT1L, which methylates histone H3 lysine 79 (H3K79). Af9 association with DOT1L enhances methylation of H3K79 at the TBR1 transcription start site, thereby interfering with RNA polymerase II (RNAPolII) activity and reducing TBR1 expression.[16] Mutants of Af9 experience increased dimethylation of H3K79 and increased TBR1 expression.[16] # Clinical significance TBR1 has been implicated in alterations in the brain that may lead to Alzheimer's Disease (AD) and Parkinson's Disease (PD). TBR1 expressing mice showed that cholinergic neurons of the basal forebrain (ChBF), the degeneration of which are involved in the development of AD and PD, migrate from the ventral pallium to the subpallium. This was confirmed using TBR1 null mice. In the future, the researchers plan to explore the role of amyloid precursor protein (APP) in neuronal migration and linkage to these diseases.[17] Reduced function of NMDA receptors play a role in schizophrenia. This diminished function of NMDA receptor may be correlated with the reduced expression of the NMDA receptor 2B subunit (NR2b), which has also been linked to schizophrenia. TBR1, in complex with the protein, CINAP, is responsible for regulating transcription of the NR2b gene. It was hypothesized in one 2010 study that reduced TBR1 and CINAP expression may be responsible for the reduced expression of the NR2b subunit observed in brains of postmortem schizophrenics. However, TBR1 and CINAP expression were not significantly reduced in the postmortem brains, suggesting that synthesis and processing of NR2b via TBR1 is not responsible for reduced NR2b expression in schizophrenics.[18] TBR1 expression has been shown to be downregulated by embryonic exposure to cocaine. Prenatal cocaine exposure in a mouse model caused a decrease in both GABA neuron migration from the basal to the dorsal forebrain and radial neuron migration in the dorsal forebrain. This exposure also decreased TBR1 and TBR2 expression. However, further research showed that cocaine exposure only delayed TBR1 expression and did not cause permanent downregulation. Therefore, in models of prenatal cocaine exposure both migration and maturation of these progenitor cells is delayed.[19] TBR1 is also used in immunohistochemical techniques in neurological research. It has been used to identify layer VI developing cortical neurons as well as the prethalamic eminence, pallium, and dorsal forebrain. The presence of TBR1 in stem cells responding to telencephalon injury implicates the normal function of these cells in this region of the brain.[20] Mutations of this gene have also been associated with medulloblastoma.[21]

https://www.wikidoc.org/index.php/TBR1

afbdea321d0ee17d1fbbe3b53a8fc028914690d1

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TBX1

TBX1 T-box transcription factor TBX1 also known as T-box protein 1 and testis-specific T-box protein is a protein that in humans is encoded by the TBX1 gene. Genes in the T-box family are transcription factors that play important roles in the formation of tissues and organs during embryonic development. To carry out these roles, proteins made by this gene family bind to specific areas of DNA called T-box binding element (TBE) to control the expression of target genes. # Gene The TBX1 gene is located on the long (q) arm of chromosome 22 at position 11.21, from base pair 18,118,779 to base pair 18,145,669. # Function The T-box 1 protein appears to be necessary for the normal development of large arteries that carry blood out of the heart, muscles and bones of the face and neck, and glands such as the thymus and parathyroid. Although the T-box 1 protein acts as a transcription factor, it is not yet known which genes are regulated by the protein. # Clinical significance Most cases of 22q11.2 deletion syndrome are caused by the deletion of a small piece of chromosome 22. This region of the chromosome contains about 30 genes, including the TBX1 gene. In a small number of affected individuals without a chromosome 22 deletion, mutations in the TBX1 gene are thought to be responsible for the characteristic signs and symptoms of the syndrome. Of the three known mutations, two mutations change one amino acid (a building block of proteins) in the T-box 1 protein. The third mutation deletes a single amino acid from the protein. These mutations likely disrupt the ability of the T-box 1 protein to bind to DNA and regulate the activity of other genes. Loss of the TBX1 gene, due to either a mutation in the gene or a deletion of part of chromosome 22, is responsible for many of the features of 22q11.2 deletion syndrome. Specifically, a loss of the TBX1 gene is associated with heart defects, an opening in the roof of the mouth (a cleft palate), distinctive facial features, and low calcium levels, but does not appear to cause learning disabilities.

TBX1 T-box transcription factor TBX1 also known as T-box protein 1 and testis-specific T-box protein is a protein that in humans is encoded by the TBX1 gene.[1] Genes in the T-box family are transcription factors that play important roles in the formation of tissues and organs during embryonic development.[2] To carry out these roles, proteins made by this gene family bind to specific areas of DNA called T-box binding element (TBE)[2] to control the expression of target genes. # Gene The TBX1 gene is located on the long (q) arm of chromosome 22 at position 11.21, from base pair 18,118,779 to base pair 18,145,669.[1] # Function The T-box 1 protein appears to be necessary for the normal development of large arteries that carry blood out of the heart, muscles and bones of the face and neck, and glands such as the thymus and parathyroid.[3][4] Although the T-box 1 protein acts as a transcription factor, it is not yet known which genes are regulated by the protein. # Clinical significance Most cases of 22q11.2 deletion syndrome are caused by the deletion of a small piece of chromosome 22. This region of the chromosome contains about 30 genes, including the TBX1 gene. In a small number of affected individuals without a chromosome 22 deletion, mutations in the TBX1 gene are thought to be responsible for the characteristic signs and symptoms of the syndrome. Of the three known mutations, two mutations change one amino acid (a building block of proteins) in the T-box 1 protein. The third mutation deletes a single amino acid from the protein. These mutations likely disrupt the ability of the T-box 1 protein to bind to DNA and regulate the activity of other genes.[5][6][7] Loss of the TBX1 gene, due to either a mutation in the gene or a deletion of part of chromosome 22, is responsible for many of the features of 22q11.2 deletion syndrome. Specifically, a loss of the TBX1 gene is associated with heart defects, an opening in the roof of the mouth (a cleft palate), distinctive facial features, and low calcium levels, but does not appear to cause learning disabilities.[8][9]

https://www.wikidoc.org/index.php/TBX1

229d282246d5a3d03163019c06a94323d395043b

wikidoc

TBX2

TBX2 T-box transcription factor 2 Tbx2 is a transcription factor that is encoded by the Tbx2 gene on chromosome 17q21-22 in humans. This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. Tbx2 and Tbx3 are the only T-box transcription factors that act as transcriptional repressors rather than transcriptional activators, and are closely related in terms of development and tumorigenesis. This gene plays a significant role in embryonic and fetal development through control of gene expression, and also has implications in various cancers. Tbx2 is associated with numerous signaling pathways, BMP, TGFβ, Wnt, and FGF, which allow for patterning and proliferation during organogenesis in fetal development. # Role in development During fetal development, the relationship of Tbx2 to FGF, BMP, and Wnt signaling pathways indicates its extensive control in development of various organ systems. It functions predominantly in the patterning of organ development rather than tissue proliferation. Tbx2 has implications in limb development, atrioventricular development of the heart, and development of the anterior brain tissues. During limb bud development, Shh and FGF signaling stimulate the outgrowth of the limb. At a certain point, Tbx2 concentrations are such that the signaling of Shh and FGF are terminated, halting further progression and outgrowth of the limb development. This occurs directly through Tbx2 repressing the expression of Grem1, creating a negative Grem1 zone, thereby disrupting the outgrowth signaling by Shh and FGF. Cardiac development is heavily regulated and requires the development of the four cardiac chambers, septum, and various valve components for outflow and inflow. In heart development, Tbx2 is up-regulated by BMP2 to stimulate atrioventricular development. The development of a Tbx2 knockout mouse model allowed for the determination of specific roles of Tbx2 in cardiac development, and scientists determined Tbx2 and Tbx3 to be redundant in much of heart development. Further, the use of these knockout models determined the significance of Tbx2 in the BMP signaling pathway for development of the atrioventricular canal, atrioventricular nodal phenotype, and atrioventricular cushion. The atrioventricular canal signaling cascade involves the atrial natriuretic factor gene (ANF). This gene is one of the first hallmarks of chamber formation in the developing myocardium. A small fragment within this gene can repress the promoter of cardiac troponin I (cTnI) selectively in the atrioventricular canal. T-box factor and NK2-homeobox factor binding element are involved in the repression of the atrioventricular canal without affecting its chamber activity. Tbx2 forms a complex with Nkx2.5 on the ANF gene to repress its promoter activity, so that the gene’s expression is inhibited in the atrioventricular canal during chamber differentiation.The atrioventricular canal is also the origin of the atrioventricular nodal axis and helps eventually coordinate the beating heart. The role of Tbx2 in cushion formation in the developing heart is by working with Tbx3 to trigger a feed-forward loop with BMP2 for the coordinated development of these cushions. Tbx2 has also been found to temporally suppress the proliferation and differentiation a subset of the primary myocardial cells. Finally, during anterior brain development, BMP stimulates the expression of Tbx2, which suppresses FGF signaling. This suppression of FGF signaling further represses the expression of Flrt3, which is necessary for anterior brain development. # Associated congenital defects It is known that Tbx2 functions in a dose-dependent manner; therefore, duplication or deletion of the region encompassing Tbx2 can cause various congenital defects, including: microcephaly, various ventricular-septal defects, and skeletal abnormalities. Some specific abnormalities are discussed further below. ## Abnormalities of the digits During limb bud development, down-regulation of Tbx2 fails to inhibit Shh/FGF4 signaling; therefore, resulting in increased limb bud size and duplication of the 4th digit, polydactyly. Opposite this, when Tbx2 is over expressed or duplicated, limb buds are smaller and can have reduced digit number because of the early termination of Shh and FGF4 signaling. ## Ventricular septal defects This is a broad category encompassing many more specific congenital heart defects. Of those related to Tbx2, some are caused by duplication, or over expression, of Tbx2, and others are caused by deletion of the Tbx2 gene region. For example, patients with a duplication of the Tbx2 gene region have presented with atrioventricular abnormalities including: interventricular septal defect, patent foramen ovale, aortic coarctation, tricuspid valve insufficiency, and mitral valve stenosis. Contrary, those with Tbx2 gene deletion have presented with pulmonary hypertension and other heart defects, but is less reported. # Role in tumorigenesis Tbx2 has been implicated in cancers associated with the lung, breast, bone, pancreas, and melanoma. It is known to be over-expressed in this group of cancers, altering cell-signaling pathways leading to tumorigenesis. Several pathways have been suggested and studied using mouse knockout models of genes within the signaling pathways. Currently, research using the knockout model of Tbx2 for study of tumorigenesis is limited. p14ARF/MDM2/p35/p21CIP1 Pathway. When up-regulated, Tbx2 inhibits p21CIP1. p21CIP1 is necessary for tissue senescence, and when compromised, leaves the tissue vulnerable to tumor-promoting signals. Wnt/beta-catenin Pathway. The role of Tbx2 in Wnt signaling has yet to be confirmed; however, up-regulation of Tbx2 in the beta-catenin signaling pathway leads to loss of the adhesion molecule E-cadherin. This returns cells to a mesenchymal state, and facilitates invasion of tumor cells. EGR1 Signaling Pathway. Finally, Tbx2 up-regulation increases its interaction with EGR1. EGR1 represses NDGR1 to increase cell proliferation, resulting in metastasis or tumor development. Together, the up-regulation of Tbx2 on these signaling pathways can lead to development of malignant tumors. # Cancer treatment target Understanding the signaling pathways, and the role of Tbx2 in tumorigenesis, can aid in developing gene-targeted cancer treatments. Because Tbx2 is up-regulated in various types of cancer cells in multiple organ systems, the potential for gene therapy is optimistic. Scientists are interested in targeting a small domain of Tbx2 and Tbx3 to reduce its expression, and utilize small peptides known to suppress tumor genes to inhibit proliferation. An in vitro study using a cell line of human prostate cancer blocked endogenous Tbx2 using Tbx2 dominant-negative retroviral vectors found reduced tumor cell proliferation. Further, the same study suggests targeting WNT3A because of its role in cell-signaling with Tbx2, by utilizing a WNT antagonist such as SFRP-2. Because somatic cells have low expression of Tbx2, a targeted Tbx2 gene treatment would leave healthy somatic cells unharmed, thereby providing a treatment with low toxicity and negative side effects. Much research is still required to determine the efficacy of these specific gene targets to anti-cancer treatments.

TBX2 T-box transcription factor 2 Tbx2 is a transcription factor that is encoded by the Tbx2 gene on chromosome 17q21-22 in humans.[1][2][3] This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. Tbx2 and Tbx3 are the only T-box transcription factors that act as transcriptional repressors rather than transcriptional activators, and are closely related in terms of development and tumorigenesis.[4] This gene plays a significant role in embryonic and fetal development through control of gene expression, and also has implications in various cancers. Tbx2 is associated with numerous signaling pathways, BMP, TGFβ, Wnt, and FGF, which allow for patterning and proliferation during organogenesis in fetal development.[4] # Role in development During fetal development, the relationship of Tbx2 to FGF, BMP, and Wnt signaling pathways indicates its extensive control in development of various organ systems. It functions predominantly in the patterning of organ development rather than tissue proliferation. Tbx2 has implications in limb development, atrioventricular development of the heart, and development of the anterior brain tissues.[5][6][7] During limb bud development, Shh and FGF signaling stimulate the outgrowth of the limb. At a certain point, Tbx2 concentrations are such that the signaling of Shh and FGF are terminated, halting further progression and outgrowth of the limb development. This occurs directly through Tbx2 repressing the expression of Grem1, creating a negative Grem1 zone, thereby disrupting the outgrowth signaling by Shh and FGF.[5] Cardiac development is heavily regulated and requires the development of the four cardiac chambers, septum, and various valve components for outflow and inflow. In heart development, Tbx2 is up-regulated by BMP2 to stimulate atrioventricular development.[6] The development of a Tbx2 knockout mouse model allowed for the determination of specific roles of Tbx2 in cardiac development, and scientists determined Tbx2 and Tbx3 to be redundant in much of heart development.[6] Further, the use of these knockout models determined the significance of Tbx2 in the BMP signaling pathway for development of the atrioventricular canal, atrioventricular nodal phenotype, and atrioventricular cushion.[6] The atrioventricular canal signaling cascade involves the atrial natriuretic factor gene (ANF). This gene is one of the first hallmarks of chamber formation in the developing myocardium. A small fragment within this gene can repress the promoter of cardiac troponin I (cTnI) selectively in the atrioventricular canal. T-box factor and NK2-homeobox factor binding element are involved in the repression of the atrioventricular canal without affecting its chamber activity. Tbx2 forms a complex with Nkx2.5 on the ANF gene to repress its promoter activity, so that the gene’s expression is inhibited in the atrioventricular canal during chamber differentiation.[8]The atrioventricular canal is also the origin of the atrioventricular nodal axis and helps eventually coordinate the beating heart. The role of Tbx2 in cushion formation in the developing heart is by working with Tbx3 to trigger a feed-forward loop with BMP2 for the coordinated development of these cushions.[9] Tbx2 has also been found to temporally suppress the proliferation and differentiation a subset of the primary myocardial cells.[10] Finally, during anterior brain development, BMP stimulates the expression of Tbx2, which suppresses FGF signaling. This suppression of FGF signaling further represses the expression of Flrt3, which is necessary for anterior brain development. # Associated congenital defects It is known that Tbx2 functions in a dose-dependent manner; therefore, duplication or deletion of the region encompassing Tbx2 can cause various congenital defects, including: microcephaly, various ventricular-septal defects, and skeletal abnormalities.[11][12][13] Some specific abnormalities are discussed further below. ## Abnormalities of the digits During limb bud development, down-regulation of Tbx2 fails to inhibit Shh/FGF4 signaling; therefore, resulting in increased limb bud size and duplication of the 4th digit, polydactyly.[5] Opposite this, when Tbx2 is over expressed or duplicated, limb buds are smaller and can have reduced digit number because of the early termination of Shh and FGF4 signaling.[5] ## Ventricular septal defects This is a broad category encompassing many more specific congenital heart defects. Of those related to Tbx2, some are caused by duplication, or over expression, of Tbx2, and others are caused by deletion of the Tbx2 gene region. For example, patients with a duplication of the Tbx2 gene region have presented with atrioventricular abnormalities including: interventricular septal defect, patent foramen ovale, aortic coarctation, tricuspid valve insufficiency, and mitral valve stenosis.[13] Contrary, those with Tbx2 gene deletion have presented with pulmonary hypertension and other heart defects, but is less reported.[14][12] # Role in tumorigenesis Tbx2 has been implicated in cancers associated with the lung, breast, bone, pancreas, and melanoma. It is known to be over-expressed in this group of cancers, altering cell-signaling pathways leading to tumorigenesis. Several pathways have been suggested and studied using mouse knockout models of genes within the signaling pathways. Currently, research using the knockout model of Tbx2 for study of tumorigenesis is limited. p14ARF/MDM2/p35/p21CIP1 Pathway. When up-regulated, Tbx2 inhibits p21CIP1. p21CIP1 is necessary for tissue senescence, and when compromised, leaves the tissue vulnerable to tumor-promoting signals.[15] Wnt/beta-catenin Pathway. The role of Tbx2 in Wnt signaling has yet to be confirmed; however, up-regulation of Tbx2 in the beta-catenin signaling pathway leads to loss of the adhesion molecule E-cadherin.[16] This returns cells to a mesenchymal state, and facilitates invasion of tumor cells. EGR1 Signaling Pathway. Finally, Tbx2 up-regulation increases its interaction with EGR1. EGR1 represses NDGR1 to increase cell proliferation, resulting in metastasis or tumor development.[17] Together, the up-regulation of Tbx2 on these signaling pathways can lead to development of malignant tumors. # Cancer treatment target Understanding the signaling pathways, and the role of Tbx2 in tumorigenesis, can aid in developing gene-targeted cancer treatments. Because Tbx2 is up-regulated in various types of cancer cells in multiple organ systems, the potential for gene therapy is optimistic. Scientists are interested in targeting a small domain of Tbx2 and Tbx3 to reduce its expression, and utilize small peptides known to suppress tumor genes to inhibit proliferation. An in vitro study using a cell line of human prostate cancer blocked endogenous Tbx2 using Tbx2 dominant-negative retroviral vectors found reduced tumor cell proliferation.[18] Further, the same study suggests targeting WNT3A because of its role in cell-signaling with Tbx2, by utilizing a WNT antagonist such as SFRP-2. Because somatic cells have low expression of Tbx2, a targeted Tbx2 gene treatment would leave healthy somatic cells unharmed, thereby providing a treatment with low toxicity and negative side effects.[4] Much research is still required to determine the efficacy of these specific gene targets to anti-cancer treatments.

https://www.wikidoc.org/index.php/TBX2

49ae8e1e97421c4a848c9c17236f6789071cb7f2

wikidoc

TBX6

TBX6 T-box 6 is a protein that in humans is encoded by the TBX6 gene. # Function This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. Knockout studies in mice indicate that this gene is important for specification of paraxial mesoderm structures. Tbx6 is also required for the segmentation of the paraxial mesoderm into somites, and for the normal development of the dermomyotome in zebrafish. In the absence of Tbx6, the central dermomyotome of zebrafish fails to develop. Tbx6 functions in a gene regulatory network with mesp-b and ripply1.

TBX6 T-box 6 is a protein that in humans is encoded by the TBX6 gene.[1] # Function This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. Knockout studies in mice indicate that this gene is important for specification of paraxial mesoderm structures.[1] Tbx6 is also required for the segmentation of the paraxial mesoderm into somites, and for the normal development of the dermomyotome in zebrafish. In the absence of Tbx6, the central dermomyotome of zebrafish fails to develop.[2] Tbx6 functions in a gene regulatory network with mesp-b and ripply1.[3]

https://www.wikidoc.org/index.php/TBX6

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wikidoc

TCF3

TCF3 Transcription factor 3 (E2A immunoglobulin enhancer-binding factors E12/E47), also known as TCF3, is a protein that in humans is encoded by the TCF3 gene. TCF3 has been shown to directly enhance Hes1 (a well-known target of Notch signaling) expression. # Function This gene encodes a member of the E protein (class I) family of helix-loop-helix transcription factors. The 9aaTAD transactivation domains of E proteins and MLL are very similar and both bind to the KIX domain of general transcriptional mediator CBP. E proteins activate transcription by binding to regulatory E-box sequences on target genes as heterodimers or homodimers, and are inhibited by heterodimerization with inhibitor of DNA-binding (class IV) helix-loop-helix proteins. E proteins play a critical role in lymphopoiesis, and the encoded protein is required for B and T lymphocyte development. 9aaTADs in the E protein family E2A and MLL binding to the KIX domain of CBP This gene regulates many developmental patterning processes such as lymphocyte and central nervous system (CNS) development. E proteins are involved in the development of lymphocytes. They initiate transcription by binding to regulatory E-box sequences on target genes. # Clinical significance Deletion of this gene or diminished activity of the encoded protein may play a role in lymphoid malignancies. This gene is also involved in several chromosomal translocations that are associated with lymphoid malignancies including pre-B-cell acute lymphoblastic leukemia (t(1;19), with PBX1 and t(17;19), with HLF), childhood leukemia (t(19;19), with TFPT) and acute leukemia (t(12;19), with ZNF384). # Interactions TCF3 has been shown to interact with: - CBFA2T3, - CREBBP, - ELK3, - EP300, - ID3, - LDB1, - LMX1A, - LYL1, - MAPKAPK3, - MyoD, - Myogenin, - PCAF, - TAL1 - TWIST1, and - UBE2I.

TCF3 Transcription factor 3 (E2A immunoglobulin enhancer-binding factors E12/E47), also known as TCF3, is a protein that in humans is encoded by the TCF3 gene.[1][2][3] TCF3 has been shown to directly enhance Hes1 (a well-known target of Notch signaling) expression.[4] # Function This gene encodes a member of the E protein (class I) family of helix-loop-helix transcription factors. The 9aaTAD transactivation domains of E proteins and MLL are very similar and both bind to the KIX domain of general transcriptional mediator CBP.[5][6] E proteins activate transcription by binding to regulatory E-box sequences on target genes as heterodimers or homodimers, and are inhibited by heterodimerization with inhibitor of DNA-binding (class IV) helix-loop-helix proteins. E proteins play a critical role in lymphopoiesis, and the encoded protein is required for B and T lymphocyte development.[1] 9aaTADs in the E protein family E2A and MLL binding to the KIX domain of CBP This gene regulates many developmental patterning processes such as lymphocyte and central nervous system (CNS) development. E proteins are involved in the development of lymphocytes.[7] They initiate transcription by binding to regulatory E-box sequences on target genes. # Clinical significance Deletion of this gene or diminished activity of the encoded protein may play a role in lymphoid malignancies. This gene is also involved in several chromosomal translocations that are associated with lymphoid malignancies including pre-B-cell acute lymphoblastic leukemia (t(1;19), with PBX1 and t(17;19), with HLF),[8] childhood leukemia (t(19;19), with TFPT) and acute leukemia (t(12;19), with ZNF384).[1] # Interactions TCF3 has been shown to interact with: - CBFA2T3,[9] - CREBBP,[10] - ELK3,[11] - EP300,[10] - ID3,[12][13] - LDB1,[9] - LMX1A,[14] - LYL1,[15] - MAPKAPK3,[16] - MyoD,[13][17] - Myogenin,[13][18] - PCAF,[10] - TAL1[9][19] - TWIST1,[20] and - UBE2I.[21]

https://www.wikidoc.org/index.php/TCF3

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wikidoc

TCF4

TCF4 Transcription factor 4 (TCF-4) also known as immunoglobulin transcription factor 2 (ITF-2) is a protein that in humans is encoded by the TCF4 gene located on chromosome 18q21.2. # Function TCF4 proteins act as transcription factors which will bind to the immunoglobulin enhancer mu-E5/kappa-E2 motif. TCF4 activates transcription by binding to the E-box (5’-CANNTG-3’) found usually on SSTR2-INR, or somatostatin receptor 2 initiator element. TCF4 is primarily involved in neurological development of the fetus during pregnancy by initiating neural differentiation by binding to DNA. It is found in the central nervous system, somites, and gonadal ridge during early development. Later in development it will be found in the thyroid, thymus, and kidneys while in adulthood TCF4 it is found in lymphocytes, muscles, and gastrointestinal system. # Clinical significance Mutations in TCF4 cause Pitt-Hopkins Syndrome (PTHS). These mutations cause TCF4 proteins to not bind to DNA properly and control the differentiation of the nervous system. In most cases that have been studied, the mutations were de novo, meaning it was a new mutation not found in other family members of the patient. Common symptoms of Pitt-Hopkins Syndrome include a wide mouth, gastrointestinal problems, developmental delay of fine motor skills, speech and breathing problems, epilepsy, and other brain defects.

TCF4 Transcription factor 4 (TCF-4) also known as immunoglobulin transcription factor 2 (ITF-2) is a protein that in humans is encoded by the TCF4 gene located on chromosome 18q21.2.[1] # Function TCF4 proteins act as transcription factors which will bind to the immunoglobulin enhancer mu-E5/kappa-E2 motif. TCF4 activates transcription by binding to the E-box (5’-CANNTG-3’) found usually on SSTR2-INR, or somatostatin receptor 2 initiator element. TCF4 is primarily involved in neurological development of the fetus during pregnancy by initiating neural differentiation by binding to DNA. It is found in the central nervous system, somites, and gonadal ridge during early development. Later in development it will be found in the thyroid, thymus, and kidneys while in adulthood TCF4 it is found in lymphocytes, muscles, and gastrointestinal system.[2][3] # Clinical significance Mutations in TCF4 cause Pitt-Hopkins Syndrome (PTHS). These mutations cause TCF4 proteins to not bind to DNA properly and control the differentiation of the nervous system. In most cases that have been studied, the mutations were de novo, meaning it was a new mutation not found in other family members of the patient. Common symptoms of Pitt-Hopkins Syndrome include a wide mouth, gastrointestinal problems, developmental delay of fine motor skills, speech and breathing problems, epilepsy, and other brain defects.[4][5]

https://www.wikidoc.org/index.php/TCF4

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wikidoc

TDP1

TDP1 Tyrosyl-DNA phosphodiesterase 1 is an enzyme that in humans is encoded by the TDP1 gene. The protein encoded by this gene is involved in repairing stalled topoisomerase I-DNA complexes by catalyzing the hydrolysis of the phosphodiester bond between the tyrosine residue of Type I topoisomerase and the 3-prime phosphate of DNA. This protein may also remove glycolate from single-stranded DNA containing 3-prime phosphoglycolate, suggesting a role in repair of free-radical mediated DNA double-strand breaks. This gene is a member of the phospholipase D family and contains two PLD phosphodiesterase domains. Mutations in this gene are associated with the disease spinocerebellar ataxia with axonal neuropathy (SCAN1). While several transcript variants may exist for this gene, the full-length natures of only two have been described to date. These two represent the major variants of this gene and encode the same isoform.

TDP1 Tyrosyl-DNA phosphodiesterase 1 is an enzyme that in humans is encoded by the TDP1 gene.[1][2][3] The protein encoded by this gene is involved in repairing stalled topoisomerase I-DNA complexes by catalyzing the hydrolysis of the phosphodiester bond between the tyrosine residue of Type I topoisomerase and the 3-prime phosphate of DNA. This protein may also remove glycolate from single-stranded DNA containing 3-prime phosphoglycolate, suggesting a role in repair of free-radical mediated DNA double-strand breaks. This gene is a member of the phospholipase D family and contains two PLD phosphodiesterase domains. Mutations in this gene are associated with the disease spinocerebellar ataxia with axonal neuropathy (SCAN1). While several transcript variants may exist for this gene, the full-length natures of only two have been described to date. These two represent the major variants of this gene and encode the same isoform.[3]

https://www.wikidoc.org/index.php/TDP1

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wikidoc

TECR

TECR Trans-2,3-enoyl-CoA reductase is an enzyme that in humans is encoded by the TECR gene. This gene encodes a multi-pass membrane protein that resides in the endoplasmic reticulum, and belongs to the steroid 5-alpha reductase family. The elongation of microsomal long and very long chain fatty acid consists of 4 sequential reactions. This protein catalyzes the final step, reducing trans-2,3-enoyl-CoA to saturated acyl-CoA. Alternatively spliced transcript variants have been found for this gene. # Clinical relevance Mutations in this gene have been shown to cause non-syndromic mental retardation.

TECR Trans-2,3-enoyl-CoA reductase is an enzyme that in humans is encoded by the TECR gene.[1] This gene encodes a multi-pass membrane protein that resides in the endoplasmic reticulum, and belongs to the steroid 5-alpha reductase family. The elongation of microsomal long and very long chain fatty acid consists of 4 sequential reactions. This protein catalyzes the final step, reducing trans-2,3-enoyl-CoA to saturated acyl-CoA. Alternatively spliced transcript variants have been found for this gene.[1] # Clinical relevance Mutations in this gene have been shown to cause non-syndromic mental retardation.[2]

https://www.wikidoc.org/index.php/TECR

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TFAM

TFAM Mitochondrial transcription factor A, abbreviated as TFAM or mtTFA, is a protein that in humans is encoded by the TFAM gene. # Function This gene encodes a mitochondrial transcription factor that is a key activator of mitochondrial transcription as well as a participant in mitochondrial genome replication. TFAM binds mitochondrial promoter DNA to aid transcription of the mitochondrial genome. Studies in mice have demonstrated that this gene product is required to regulate the mitochondrial genome copy number and is essential for embryonic development. A mouse model for Kearns-Sayre syndrome was produced when expression of this gene was eliminated by targeted disruption in heart and muscle cells. TFAM is a double box High-mobility group DNA-binding and bending protein. # Interactions TFAM has been shown to interact with TFB1M.

TFAM Mitochondrial transcription factor A, abbreviated as TFAM or mtTFA, is a protein that in humans is encoded by the TFAM gene.[1][2] # Function This gene encodes a mitochondrial transcription factor that is a key activator of mitochondrial transcription as well as a participant in mitochondrial genome replication. TFAM binds mitochondrial promoter DNA to aid transcription of the mitochondrial genome. Studies in mice have demonstrated that this gene product is required to regulate the mitochondrial genome copy number and is essential for embryonic development. A mouse model for Kearns-Sayre syndrome was produced when expression of this gene was eliminated by targeted disruption in heart and muscle cells.[2] TFAM is a double box High-mobility group DNA-binding and bending protein.[3] # Interactions TFAM has been shown to interact with TFB1M.[4]

https://www.wikidoc.org/index.php/TFAM

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wikidoc

TFE3

TFE3 Transcription factor E3 is a protein that in humans is encoded by the TFE3 gene. # Function TFE3, a member of the helix-loop-helix family of transcription factors, binds to the mu-E3 motif of the immunoglobulin heavy-chain enhancer and is expressed in many cell types (Henthorn et al., 1991). # Interactions TFE3 has been shown to interact with: - E2F3, - Microphthalmia-associated transcription factor, and - Mothers against decapentaplegic homolog 3 # Translocations A proportion of renal carcinomas (RCC) that occur in young patients are associated with translocations involving the TFE3 gene at chromosome Xp11.2 PRCC

TFE3 Transcription factor E3 is a protein that in humans is encoded by the TFE3 gene.[1][2][3] # Function TFE3, a member of the helix-loop-helix family of transcription factors, binds to the mu-E3 motif of the immunoglobulin heavy-chain enhancer and is expressed in many cell types (Henthorn et al., 1991).[supplied by OMIM][3] # Interactions TFE3 has been shown to interact with: - E2F3,[4] - Microphthalmia-associated transcription factor,[5][6] and - Mothers against decapentaplegic homolog 3[7][8] # Translocations A proportion of renal carcinomas (RCC) that occur in young patients are associated with translocations involving the TFE3 gene at chromosome Xp11.2 PRCC

https://www.wikidoc.org/index.php/TFE3

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wikidoc

TFEB

TFEB Transcription factor EB is a protein that in humans is encoded by the TFEB gene. # Function TFEB is a master gene for lysosomal biogenesis. It encodes a transcription factor that coordinates expression of lysosomal hydrolases, membrane proteins and genes involved in autophagy. Upon nutrient depletion and under aberrant lysosomal storage conditions such as in lysosomal storage diseases, TFEB translocates from the cytoplasm to the nucleus, resulting in the activation of its target genes. TFEB overexpression in cultured cells induces lysosomal biogenesis, exocytosis and autophagy. Viral-mediated TFEB overexpression in cellular and mouse models of lysosomal storage disorders and in common neurodegenerative diseases such as Huntington, Parkinson and Alzheimer diseases, resulted in intracellular clearance of accumulating molecules and rescue of disease phenotypes. TFEB is activated by PGC1-alpha and promotes reduction of htt aggregation and neurotoxicity in a mouse model of Huntington disease. TFEB overexpression has been found in patients with renal cell carcinoma and pancreatic cancer and was shown to promote tumorogenesis via induction of varius oncogenic signals. Nuclear localization and activity of TFEB is inhibited by serine phosphorylation by mTORC1 and extracellular signal–regulated kinase 2 (ERK2). mTORC1 phosphorylation of TFEB occurs at the lysosomal surface, both of which are localized there by interaction with the Rag GTPases. Phosphorylated TFEB is then retained in the cytosol by interaction with 14-3-3 proteins. These kinases are tuned to the levels of extracellular nutrients suggesting a coordination in regulation of autophagy and lysosomal biogenesis and partnership of two distinct cellular organelles. Nutrient depletion induces TFEB dephosphorylation and subsequent nuclear translocation via the phosphatase calcineurin. TFEB nuclear export is mediated by CRM1 and is dependent on phosphorylation. TFEB is also a target of the protein kinase AKT/PKB. AKT/PKB phosphorylates TFEB at serine 467 and inhibits TFEB nuclear translocation. Pharmacological inhibition of AKT/PKB activates TFEB, promotes lysosome biogenesis and autophagy, and ameliorates neuropathology in a mouse model of Juvenile Batten disease. TFEB is activated in Trex1-deficient cells via inhibition of mTORC1 activity, resulting in an expanded lysosomal compartment.

TFEB Transcription factor EB is a protein that in humans is encoded by the TFEB gene.[1][2] # Function TFEB is a master gene for lysosomal biogenesis.[3] It encodes a transcription factor that coordinates expression of lysosomal hydrolases, membrane proteins and genes involved in autophagy.[3][4] Upon nutrient depletion and under aberrant lysosomal storage conditions such as in lysosomal storage diseases, TFEB translocates from the cytoplasm to the nucleus, resulting in the activation of its target genes.[3][4] TFEB overexpression in cultured cells induces lysosomal biogenesis, exocytosis and autophagy. [3][4][5] Viral-mediated TFEB overexpression in cellular and mouse models of lysosomal storage disorders and in common neurodegenerative diseases such as Huntington, Parkinson and Alzheimer diseases, resulted in intracellular clearance of accumulating molecules and rescue of disease phenotypes.[3][5][6][7][8] TFEB is activated by PGC1-alpha and promotes reduction of htt aggregation and neurotoxicity in a mouse model of Huntington disease.[9] TFEB overexpression has been found in patients with renal cell carcinoma and pancreatic cancer and was shown to promote tumorogenesis via induction of varius oncogenic signals.[10][11][12] Nuclear localization and activity of TFEB is inhibited by serine phosphorylation by mTORC1 and extracellular signal–regulated kinase 2 (ERK2). [4][13][14][15] mTORC1 phosphorylation of TFEB occurs at the lysosomal surface, both of which are localized there by interaction with the Rag GTPases. Phosphorylated TFEB is then retained in the cytosol by interaction with 14-3-3 proteins.[14][16][15] These kinases are tuned to the levels of extracellular nutrients suggesting a coordination in regulation of autophagy and lysosomal biogenesis and partnership of two distinct cellular organelles.[4] Nutrient depletion induces TFEB dephosphorylation and subsequent nuclear translocation via the phosphatase calcineurin. [17] TFEB nuclear export is mediated by CRM1 and is dependent on phosphorylation.[18][19] TFEB is also a target of the protein kinase AKT/PKB.[20] AKT/PKB phosphorylates TFEB at serine 467 and inhibits TFEB nuclear translocation.[20] Pharmacological inhibition of AKT/PKB activates TFEB, promotes lysosome biogenesis and autophagy, and ameliorates neuropathology in a mouse model of Juvenile Batten disease.[20] TFEB is activated in Trex1-deficient cells via inhibition of mTORC1 activity, resulting in an expanded lysosomal compartment.[21]

https://www.wikidoc.org/index.php/TFEB

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wikidoc

TGM6

TGM6 Transglutaminase 6 is a protein that in humans is encoded by the TGM6 gene. # Function The protein encoded by this gene belongs to the transglutaminase superfamily. It catalyzes the cross-linking of proteins and the conjugation of polyamines to proteins. Mutations in this gene are associated with spinocerebellar ataxia type 35 (SCA35). Alternatively spliced transcript variants encoding different isoforms have been found for this gene. . Mutations in TGM6 cause acute myeloid leukaemia . # Model organisms Model organisms have been used in the study of TGM6 function. A conditional knockout mouse line called Tgm6tm1a(KOMP)Wtsi was generated at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Additional screens performed: - In-depth immunological phenotyping

TGM6 Transglutaminase 6 is a protein that in humans is encoded by the TGM6 gene. [1] # Function The protein encoded by this gene belongs to the transglutaminase superfamily. It catalyzes the cross-linking of proteins and the conjugation of polyamines to proteins. Mutations in this gene are associated with spinocerebellar ataxia type 35 (SCA35). Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]. Mutations in TGM6 cause acute myeloid leukaemia .[2] # Model organisms Model organisms have been used in the study of TGM6 function. A conditional knockout mouse line called Tgm6tm1a(KOMP)Wtsi was generated at the Wellcome Trust Sanger Institute.[3] Male and female animals underwent a standardized phenotypic screen[4] to determine the effects of deletion.[5][6][7][8] Additional screens performed: - In-depth immunological phenotyping[9]

https://www.wikidoc.org/index.php/TGM6

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wikidoc

TIG1

TIG1 # Overview Tazarotene-induced gene-1 (TIG1) is a protein which has been implicated as a putative tumor suppressor. It is structurally similar to the protein latexin, which has also been shown to demonstrate some tumor suppression activity (Liang et al., 2007). TIG1 is thought to be a transmembrane protein, and its mechanism of tumor suppression is largely unknown. # Structure The amino acid sequence of the protein TIG1 is as follows: N terminus-Met-Gln-Pro-Arg-Arg-Gln-Arg-Leu-Pro- Ala-Pro-Trp-Ser-Gly-Pro-Arg-Gly-Pro-Arg-Pro-Thr- Ala-Pro-Leu-Leu-Ala-Leu-Leu-Leu-Leu-Leu-Ala-Pro- Val-Ala-Ala-Pro-Ala-Gly-Ser-Gly-Gly-Pro-Asp-Asp- Pro-Gly-Gln-Pro-Gln-Asp-Ala-Gly-Val-Pro-Arg-Arg- Leu-Leu-Gln-Gln-Lys-Ala-Arg-Ala-Ala-Leu-His-Phe- Phe-Asn-Phe-Arg-Ser-Gly-Ser-Pro-Ser-Ala-Leu-Arg- Val-Leu-Ala-Glu-Val-Gln-Glu-Gly-Arg-Ala-Trp-Ile- Asn-Pro-Lys-Glu-Gly-Cys-Lys-Val-His-Val-Val-Phe- Ser-Thr-Glu-Arg-Tyr-Asn-Pro-Glu-Ser-Leu-Leu-Gln- Glu-Gly-Glu-Gly-Arg-Leu-Gly-Lys-Cys-Ser-Ala-Arg- Val-Phe-Phe-Lys-Asn-Gln-Lys-Pro-Arg-Pro-Thr-Ile- Asn-Val-Thr-Cys-Thr-Arg-Leu-Ile-Glu-Lys-Lys-Lys -Gln-Gln-Glu-Asp-Tyr-Leu-Leu-Tyr-Lys-Gln-Met-Lys- Gln-Leu-Lys-Asn-Pro-Leu-Glu-Ile-Val-Ser-Ile-Pro- Asp-Asn-His-Gly-His-Ile-Asp-Pro-Ser-Leu-Arg-Leu- Ile-Trp-Asp-Leu-Ala-Phe-Leu-Gly-Ser-Ser-Tyr-Val- Met-Trp-Glu-Met-Thr-Thr-Gln-Val-Ser-His-Tyr-Tyr- Leu-Ala-Gln-Leu-Thr-Ser-Val-Arg-Gln-Trp-Val-Arg- Lys-Thr-CTerminus. TIG1 is a transmembrane protein which contains a hyaluronic acid binding motif. This particular motif suggests that it may increase cell-to-cell contact in cells which express TIG1 (Jing et al., 2002). TIG1 is predicted to contain a membrane anchor at the N-terminus. TIG1 contains two faces: the first face contains homology to the protein latexin, and the second contains a broad basic patch. The basic face is thought to be an interaction surface. Supporting the idea of a protein interaction surface, TIG1 also contains a cis-peptide bond between isoleucine-122 and proline-123 on a protruding loop that lies on its basic face (Aagard et al., 2005). Latexin and TIG1 have approximately 30 percent homology based on primary structure; however, their three-dimensional structures are thought to be much more similar (Liang et al., 2007). Both latexin and TIG1 are thought to have descended from a common progenitor. TIG1 also shares homology with another protein, ovacalyxin-32, although the evolutionary and functional relationship between the two proteins is unclear (Gautron et al., 2001). # Function TIG1's specific functions are still in the process of being elucidated. Latexin is a structurally similar protein to TIG1. Latexin is the only mammalian carboxypeptidase inhibitor, although TIG1’s proteolytic activity remains unexplored. Using a selective subtractive differential gene display, Jing and colleagues discovered that TIG1 expression was absent from malignant prostate carcinoma cell lines but present in benign tumor lines. When highly malignant prostate cancer cells were transfected with TIG1, decreased in vitro invasiveness was measured using an extracellular matrix migration assay over a period of 48 hours. This same group of scientists performed another experiment in which TIG1 expression was restored in mice that were homozygous for the deletion of the TIG1 gene. Although the restoration of TIG1 did not prevent tumor growth in these mice, the average size of the tumors showed a 2.4 fold decrease (Jing et al., 2006). # Regulation The promoter of TIG1 is silenced by hypermethylation in gastric cancer. Promoter hypermethylation is a common mechanism for silencing tumor suppression genes. During carcinogenesis, methylation begins at the CpG island of the promoter and gradually works its way to the transcription start site, at which point it inhibits transcription of TIG1 (So et al., 2006). Additionally, the CpG promoter hypermethylation of TIG1 has also been demonstrated as an important event in the carcinogenesis of prostate adenocarcinoma (Cho et al., 2007).

TIG1 # Overview Tazarotene-induced gene-1 (TIG1) is a protein which has been implicated as a putative tumor suppressor. It is structurally similar to the protein latexin, which has also been shown to demonstrate some tumor suppression activity (Liang et al., 2007). TIG1 is thought to be a transmembrane protein, and its mechanism of tumor suppression is largely unknown. # Structure The amino acid sequence of the protein TIG1 is as follows: N terminus-Met-Gln-Pro-Arg-Arg-Gln-Arg-Leu-Pro- Ala-Pro-Trp-Ser-Gly-Pro-Arg-Gly-Pro-Arg-Pro-Thr- Ala-Pro-Leu-Leu-Ala-Leu-Leu-Leu-Leu-Leu-Ala-Pro- Val-Ala-Ala-Pro-Ala-Gly-Ser-Gly-Gly-Pro-Asp-Asp- Pro-Gly-Gln-Pro-Gln-Asp-Ala-Gly-Val-Pro-Arg-Arg- Leu-Leu-Gln-Gln-Lys-Ala-Arg-Ala-Ala-Leu-His-Phe- Phe-Asn-Phe-Arg-Ser-Gly-Ser-Pro-Ser-Ala-Leu-Arg- Val-Leu-Ala-Glu-Val-Gln-Glu-Gly-Arg-Ala-Trp-Ile- Asn-Pro-Lys-Glu-Gly-Cys-Lys-Val-His-Val-Val-Phe- Ser-Thr-Glu-Arg-Tyr-Asn-Pro-Glu-Ser-Leu-Leu-Gln- Glu-Gly-Glu-Gly-Arg-Leu-Gly-Lys-Cys-Ser-Ala-Arg- Val-Phe-Phe-Lys-Asn-Gln-Lys-Pro-Arg-Pro-Thr-Ile- Asn-Val-Thr-Cys-Thr-Arg-Leu-Ile-Glu-Lys-Lys-Lys -Gln-Gln-Glu-Asp-Tyr-Leu-Leu-Tyr-Lys-Gln-Met-Lys- Gln-Leu-Lys-Asn-Pro-Leu-Glu-Ile-Val-Ser-Ile-Pro- Asp-Asn-His-Gly-His-Ile-Asp-Pro-Ser-Leu-Arg-Leu- Ile-Trp-Asp-Leu-Ala-Phe-Leu-Gly-Ser-Ser-Tyr-Val- Met-Trp-Glu-Met-Thr-Thr-Gln-Val-Ser-His-Tyr-Tyr- Leu-Ala-Gln-Leu-Thr-Ser-Val-Arg-Gln-Trp-Val-Arg- Lys-Thr-CTerminus. TIG1 is a transmembrane protein which contains a hyaluronic acid binding motif. This particular motif suggests that it may increase cell-to-cell contact in cells which express TIG1 (Jing et al., 2002). TIG1 is predicted to contain a membrane anchor at the N-terminus. TIG1 contains two faces: the first face contains homology to the protein latexin, and the second contains a broad basic patch. The basic face is thought to be an interaction surface. Supporting the idea of a protein interaction surface, TIG1 also contains a cis-peptide bond between isoleucine-122 and proline-123 on a protruding loop that lies on its basic face (Aagard et al., 2005). Latexin and TIG1 have approximately 30 percent homology based on primary structure; however, their three-dimensional structures are thought to be much more similar (Liang et al., 2007). Both latexin and TIG1 are thought to have descended from a common progenitor. TIG1 also shares homology with another protein, ovacalyxin-32, although the evolutionary and functional relationship between the two proteins is unclear (Gautron et al., 2001). # Function TIG1's specific functions are still in the process of being elucidated. Latexin is a structurally similar protein to TIG1. Latexin is the only mammalian carboxypeptidase inhibitor, although TIG1’s proteolytic activity remains unexplored. Using a selective subtractive differential gene display, Jing and colleagues discovered that TIG1 expression was absent from malignant prostate carcinoma cell lines but present in benign tumor lines. When highly malignant prostate cancer cells were transfected with TIG1, decreased in vitro invasiveness was measured using an extracellular matrix migration assay over a period of 48 hours. This same group of scientists performed another experiment in which TIG1 expression was restored in mice that were homozygous for the deletion of the TIG1 gene. Although the restoration of TIG1 did not prevent tumor growth in these mice, the average size of the tumors showed a 2.4 fold decrease (Jing et al., 2006). # Regulation The promoter of TIG1 is silenced by hypermethylation in gastric cancer. Promoter hypermethylation is a common mechanism for silencing tumor suppression genes. During carcinogenesis, methylation begins at the CpG island of the promoter and gradually works its way to the transcription start site, at which point it inhibits transcription of TIG1 (So et al., 2006). Additionally, the CpG promoter hypermethylation of TIG1 has also been demonstrated as an important event in the carcinogenesis of prostate adenocarcinoma (Cho et al., 2007).

https://www.wikidoc.org/index.php/TIG1

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wikidoc

TLK1

TLK1 Serine/threonine-protein kinase tousled-like 1 is an enzyme that in humans is encoded by the TLK1 gene. # Function The Tousled-like kinases, first described in Arabidopsis, are nuclear serine/threonine kinases that are potentially involved in the regulation of chromatin assembly. # Interactions TLK1 has been shown to interact with ASF1B, ASF1A and TLK2.

TLK1 Serine/threonine-protein kinase tousled-like 1 is an enzyme that in humans is encoded by the TLK1 gene.[1][2][3] # Function The Tousled-like kinases, first described in Arabidopsis, are nuclear serine/threonine kinases that are potentially involved in the regulation of chromatin assembly.[supplied by OMIM][3] # Interactions TLK1 has been shown to interact with ASF1B,[4][5] ASF1A[4][6] and TLK2.[7]

https://www.wikidoc.org/index.php/TLK1

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wikidoc

TLK2

TLK2 Serine/threonine-protein kinase tousled-like 2 is an enzyme that in humans is encoded by the TLK2 gene. # Function The Tousled-like kinases, first described in Arabidopsis, are nuclear serine/threonine kinases that are potentially involved in the regulation of chromatin assembly. These are different from other "tousled" varieties, such as flock-of-seagulls, post-coitus, or the-Sean-Bean. # Interactions TLK2 has been shown to interact with TLK1, ASF1B and ASF1A.

TLK2 Serine/threonine-protein kinase tousled-like 2 is an enzyme that in humans is encoded by the TLK2 gene.[1][2][3] # Function The Tousled-like kinases, first described in Arabidopsis, are nuclear serine/threonine kinases that are potentially involved in the regulation of chromatin assembly. These are different from other "tousled" varieties, such as flock-of-seagulls, post-coitus, or the-Sean-Bean.[supplied by OMIM][3] # Interactions TLK2 has been shown to interact with TLK1,[2] ASF1B[4][5] and ASF1A.[5]

https://www.wikidoc.org/index.php/TLK2

908f34cc1df02a8c8eadb537a1c42ed24003dec5

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TLN1

TLN1 Talin-1 is a protein that in humans is encoded by the TLN1 gene. Talin-1 is ubiquitously expressed, and is localized to costamere structures in cardiac and skeletal muscle cells, and to focal adhesions in smooth muscle and non-muscle cells. Talin-1 functions to mediate cell-cell adhesion via the linkage of integrins to the actin cytoskeleton and in the activation of integrins. Altered expression of talin-1 has been observed in patients with heart failure, however no mutations in TLN1 have been linked with specific diseases. # Structure Human talin-1 is 270.0 kDa molecular weight and 2541 amino acids. The N-terminal region of talin-1 is ~50 kDa in size and homologous to members of the ERM protein family which have a globular FERM domain (residues 86-400) that links the actin cytoskeleton to adhesion proteins. In addition to F-actin, the N-terminal region of talin-1 binds layilin, β1- and β3-integrin, and focal adhesion kinase. Talin-1 N-terminal region also binds acidic phospholipids for insertion into lipid bilayers. The rod domain (>200 kDa) has considerable flexibility and houses a conserved actin binding site, three vinculin binding sites, and also has an additional integrin binding site, termed IBS2. The head and rod domains are connected by an unstructured linker region (residues 401-481), which houses several sites of phosphorylation, as well as protease cleavage. Talin-1 can homodimerize in an antiparallel fashion, however, talin-1 and its closely related counterpart, talin-2 do not form heterodimers. # Function In mammals talin-1 is ubiquitously expressed; talin-1 is found complexed to integrins and localized to intercalated discs of cardiac muscle and to costamere structures of both skeletal and cardiac muscles, in correspondence with the I-band and M-line. Talin-1 is also found at focal adhesions of smooth muscle cells and non-muscle cells. In undifferentiated cultures of myoblasts, talin-1 expression is perinuclear, and then progresses to a cytoplasmic distribution followed by a sarcomlemmal, costameric-like pattern by day 15 of differentiation. Homozygous disruption of TLN1 in mice is embryonic lethal, demonstrating that talin-1 is required for normal embryogenesis. It has been shown, however, that talin-1 expression is minor in adult cardiomyocytes, and becomes more prominent at costameres during cardiac hypertrophy induced by pharmacological and mechanical stress. The primary function of talin-1 involves the linkage of integrins to the actin cytoskeleton and in the energy-dependent activation of integrins. Functions for talin-1 in specific tissues have been illuminated through conditional knockout animals. Studies employing the conditional knockout of talin 1 in skeletal muscle have demonstrated its role in maintaining integrin attachment sites at myotendinous junctions; knockout mice develop progressive myopathy and show deficits in muscle force generation. In platelets, conditional knockout of talin-1 results in the inability to activate integrins in response to platelet agonists, resulting in mice with severe hemostatic defects and resistance to arterial thrombosis. Conditional knockout of talin-1 in cardiomyocytes shows that mice have normal cardiac function at baseline, but improved function, blunted hypertrophy, and attenuated fibrosis when subjected to pressure overload-induced cardiac hypertrophy, which correlated with blunted ERK1/2, p38, Akt, and glycogen synthase kinase 3 responses. These data suggest that upregulation of talin-1 in cardiac hypertrophy may be detrimental to cardiomyocytes function. # Clinical significance In patients with heart failure, talin-1 expression in cardiomyocytes is increased relative to control cells. # Interactions TLN1 has been shown to interact with: - ACTA1, - CD61, - ITGB1, - LAYN, - PXN, - PIP5K1C, - PTK2, - SYNM, and - VCL.

TLN1 Talin-1 is a protein that in humans is encoded by the TLN1 gene.[1][2] Talin-1 is ubiquitously expressed, and is localized to costamere structures in cardiac and skeletal muscle cells, and to focal adhesions in smooth muscle and non-muscle cells. Talin-1 functions to mediate cell-cell adhesion via the linkage of integrins to the actin cytoskeleton and in the activation of integrins. Altered expression of talin-1 has been observed in patients with heart failure, however no mutations in TLN1 have been linked with specific diseases. # Structure Human talin-1 is 270.0 kDa molecular weight and 2541 amino acids.[3] The N-terminal region of talin-1 is ~50 kDa in size and homologous to members of the ERM protein family which have a globular FERM domain (residues 86-400) that links the actin cytoskeleton to adhesion proteins.[4][5] In addition to F-actin,[6] the N-terminal region of talin-1 binds layilin,[7] β1- and β3-integrin,[8][9][10] and focal adhesion kinase.[11][12] Talin-1 N-terminal region also binds acidic phospholipids for insertion into lipid bilayers.[13][14][15] The rod domain (>200 kDa) has considerable flexibility and houses a conserved actin binding site,[6] three vinculin binding sites,[16][17][18] and also has an additional integrin binding site, termed IBS2.[19][20][21][22][23] The head and rod domains are connected by an unstructured linker region (residues 401-481), which houses several sites of phosphorylation,[24] as well as protease cleavage.[25] Talin-1 can homodimerize in an antiparallel fashion,[26] however, talin-1 and its closely related counterpart, talin-2 do not form heterodimers.[27] # Function In mammals talin-1 is ubiquitously expressed; talin-1 is found complexed to integrins and localized to intercalated discs of cardiac muscle and to costamere structures of both skeletal and cardiac muscles,[28] in correspondence with the I-band and M-line.[29][30][31] Talin-1 is also found at focal adhesions of smooth muscle cells [32] and non-muscle cells.[5] In undifferentiated cultures of myoblasts, talin-1 expression is perinuclear, and then progresses to a cytoplasmic distribution followed by a sarcomlemmal, costameric-like pattern by day 15 of differentiation.[33] Homozygous disruption of TLN1 in mice is embryonic lethal, demonstrating that talin-1 is required for normal embryogenesis.[34] It has been shown, however, that talin-1 expression is minor in adult cardiomyocytes, and becomes more prominent at costameres during cardiac hypertrophy induced by pharmacological and mechanical stress.[35] The primary function of talin-1 involves the linkage of integrins to the actin cytoskeleton and in the energy-dependent activation of integrins.[5][36] Functions for talin-1 in specific tissues have been illuminated through conditional knockout animals. Studies employing the conditional knockout of talin 1 in skeletal muscle have demonstrated its role in maintaining integrin attachment sites at myotendinous junctions; knockout mice develop progressive myopathy and show deficits in muscle force generation.[37] In platelets, conditional knockout of talin-1 results in the inability to activate integrins in response to platelet agonists, resulting in mice with severe hemostatic defects and resistance to arterial thrombosis.[38] Conditional knockout of talin-1 in cardiomyocytes shows that mice have normal cardiac function at baseline, but improved function, blunted hypertrophy, and attenuated fibrosis when subjected to pressure overload-induced cardiac hypertrophy, which correlated with blunted ERK1/2, p38, Akt, and glycogen synthase kinase 3 responses. These data suggest that upregulation of talin-1 in cardiac hypertrophy may be detrimental to cardiomyocytes function.[35] # Clinical significance In patients with heart failure, talin-1 expression in cardiomyocytes is increased relative to control cells.[35] # Interactions TLN1 has been shown to interact with: - ACTA1,[6] - CD61,[8][9] - ITGB1,[10] - LAYN,[7][39] - PXN,[40][41][42] - PIP5K1C,[43][44] - PTK2,[11][12] - SYNM,[45] and - VCL.[16][17][18]

https://www.wikidoc.org/index.php/TLN1

67223d1e80f50e13bae0d80752d7ea0b1ae8030d

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TLN2

TLN2 Talin 2 is a protein in humans that is encoded by the TLN2 gene. It belongs to the talin protein family. This gene encodes a protein related to talin 1, a cytoskeletal protein that plays a significant role in the assembly of actin filaments. Talin-2 is expressed at high levels in cardiac muscle and functions to provide linkages between the extracellular matrix and actin cytoskeleton at costamere structures to transduce force laterally. # Structure Human talin-2 is 271.4 kDa and 2542 amino acids in length. The size of talin-2 protein is similar to talin-1, and is relatively similar (74% identity, 86% similarity); the size of the talin-2 gene (200 kb) is however much larger than that of talin-1 (30 kb), due to differences in intron sizes. Talin-2 mRNA is expressed in multiple tissues, including cardiac muscle, mouse embryonic stem cells, brain, lung, skeletal muscle, kidney and testis; however expression is highest in cardiac muscle. A detailed analysis of the TLN2 gene revealed that the alternative splicing of TLN2 is complex and encodes multiple mRNA transcripts and protein isoforms. Studies revealed a promoter associated with a CpG island that accounts for most of the TLN2 expression in adult tissues. This promoter is separated from the first coding exon by approximately > 200 kb of alternatively spliced noncoding exons. The testis and kidney talin-2 isoforms lack the N-terminal 50% of the protein, and evidence suggests that this is the isoform expressed in elongating spermatids. Talin is also post-translationally modified via calpain 2-mediated cleavage, which may target it for ubiquitin-proteasome-mediated degradation and turnover of associated cell adhesion structures. # Function The expression of talin-2 in striated muscle is developmentally regulated. Undifferentiated myoblasts primarily express talin-1, and both mRNA and protein expression of talin-2 is upregulated during differentiation; ectopic expression of talin-2 in undifferentiated myoblasts dysregulates the actin cytoskeleton, demonstrating that the timing of talin-2 expression during development is critical. In mature cardiomyocytes and skeletal muscle, talin-2 is expressed at costameres and intercalated discs, thus demonstrating that talin2 links integrins and the actin cytoskeleton in stable adhesion complexes involving mature sarcomeres. Talin-2 appears to play a role in skeletal muscle development; specifically, in myoblast fusion, sarcomere assembly, and the integrity of myotendinous junctions. Ablation of both talin isoforms, talin-2 and talin-1 prevented normal myoblast fusion and sarcomere assembly, as well as assembly of integrin adhesion complexes, which was attributed to disrupted interactions between integrins and the actin cytoskeleton. The mRNA expression of talin-2 has been shown to be regulated by the muscle-specific fragile X mental retardation, autosomal homolog 1 (FXR1) protein, which binds talin2 mRNAs directly and represses translation. Knockout of FXR1 upregulates talin-2 protein, which disrupts the architecture of desmosomes and costameres in cardiac muscle. Talin-2, like talin-1 appears to join ligand-bound integrins and the actin cytoskeleton, which enhances the affinity of integrins for the extracellular matrix and catalyzes focal adhesion-dependent signaling pathways, as well as reinforces the cytoskeletal-integrin structure in response to an applied force. The strength of the interaction between talin and integrin appears to be fine-tuned through differential expression of isoforms in different tissues. The talin-2/β1D-integrin isoforms that are expressed and colocalize in striated muscle form a markedly strong interaction, and a few amino acid deletions in the β1-integrin tail can alter this interaction by 1000-fold. Talin-2 is found within the neuronal synaptic region in brain tissue, and plays a role in clathrin-mediated endocytosis, coordinating phosphatidylinositol synthesis, and modulating actin dynamics through interactions with PIP kinase type 1γ, the major phosphatidylinositol 4,5-bisphosphate-synthesizing enzyme of the brain. # Clinical significance In patients with temporal lobe epilepsy, talin-2 protein was detected in cerebrospinal fluid, whereas expression was absent in non-epileptic patients. Furthermore, postencephalitic epilepsy patients that were refractory to drug treatment exhibited markedly elevated levels of talin-2 protein in cerebrospinal fluid and reciprocally decreased levels in serum. These data suggest that talin-2 may prove useful as a biomarker for epilepsy, and may be pathologically linked to this disease. Studies have also shown that TLN2 is a direct target of miR-132, which is epigenetically silenced in prostate cancer, suggesting that talin-2 may play a role in modulating cell adhesion in prostate cancer. # Interactions TLN2 has been shown to interact with: - ACTA1, - CD61, - ITGB1, - LAYN, - PTK2,

TLN2 Talin 2 is a protein in humans that is encoded by the TLN2 gene. It belongs to the talin protein family. This gene encodes a protein related to talin 1, a cytoskeletal protein that plays a significant role in the assembly of actin filaments. Talin-2 is expressed at high levels in cardiac muscle and functions to provide linkages between the extracellular matrix and actin cytoskeleton at costamere structures to transduce force laterally.[1] # Structure Human talin-2 is 271.4 kDa and 2542 amino acids in length.[2] The size of talin-2 protein is similar to talin-1, and is relatively similar (74% identity, 86% similarity); the size of the talin-2 gene (200 kb) is however much larger than that of talin-1 (30 kb), due to differences in intron sizes.[3] Talin-2 mRNA is expressed in multiple tissues, including cardiac muscle, mouse embryonic stem cells, brain, lung, skeletal muscle, kidney and testis; however expression is highest in cardiac muscle.[3][4][5][6] A detailed analysis of the TLN2 gene revealed that the alternative splicing of TLN2 is complex and encodes multiple mRNA transcripts and protein isoforms. Studies revealed a promoter associated with a CpG island that accounts for most of the TLN2 expression in adult tissues. This promoter is separated from the first coding exon by approximately > 200 kb of alternatively spliced noncoding exons. The testis and kidney talin-2 isoforms lack the N-terminal 50% of the protein, and evidence suggests that this is the isoform expressed in elongating spermatids.[7] Talin is also post-translationally modified via calpain 2-mediated cleavage, which may target it for ubiquitin-proteasome-mediated degradation and turnover of associated cell adhesion structures.[8] # Function The expression of talin-2 in striated muscle is developmentally regulated. Undifferentiated myoblasts primarily express talin-1, and both mRNA and protein expression of talin-2 is upregulated during differentiation; ectopic expression of talin-2 in undifferentiated myoblasts dysregulates the actin cytoskeleton, demonstrating that the timing of talin-2 expression during development is critical. In mature cardiomyocytes and skeletal muscle, talin-2 is expressed at costameres and intercalated discs, thus demonstrating that talin2 links integrins and the actin cytoskeleton in stable adhesion complexes involving mature sarcomeres.[6][9] Talin-2 appears to play a role in skeletal muscle development; specifically, in myoblast fusion, sarcomere assembly, and the integrity of myotendinous junctions. Ablation of both talin isoforms, talin-2 and talin-1 prevented normal myoblast fusion and sarcomere assembly, as well as assembly of integrin adhesion complexes, which was attributed to disrupted interactions between integrins and the actin cytoskeleton.[10] The mRNA expression of talin-2 has been shown to be regulated by the muscle-specific fragile X mental retardation, autosomal homolog 1 (FXR1) protein, which binds talin2 mRNAs directly and represses translation. Knockout of FXR1 upregulates talin-2 protein, which disrupts the architecture of desmosomes and costameres in cardiac muscle.[11] Talin-2, like talin-1 appears to join ligand-bound integrins and the actin cytoskeleton, which enhances the affinity of integrins for the extracellular matrix and catalyzes focal adhesion-dependent signaling pathways,[12] as well as reinforces the cytoskeletal-integrin structure in response to an applied force.[13] The strength of the interaction between talin and integrin appears to be fine-tuned through differential expression of isoforms in different tissues. The talin-2/β1D-integrin isoforms that are expressed and colocalize in striated muscle form a markedly strong interaction, and a few amino acid deletions in the β1-integrin tail can alter this interaction by 1000-fold.[14] Talin-2 is found within the neuronal synaptic region in brain tissue, and plays a role in clathrin-mediated endocytosis, coordinating phosphatidylinositol synthesis, and modulating actin dynamics through interactions with PIP kinase type 1γ, the major phosphatidylinositol 4,5-bisphosphate-synthesizing enzyme of the brain.[15] # Clinical significance In patients with temporal lobe epilepsy, talin-2 protein was detected in cerebrospinal fluid, whereas expression was absent in non-epileptic patients.[16] Furthermore, postencephalitic epilepsy patients that were refractory to drug treatment exhibited markedly elevated levels of talin-2 protein in cerebrospinal fluid and reciprocally decreased levels in serum.[17] These data suggest that talin-2 may prove useful as a biomarker for epilepsy, and may be pathologically linked to this disease. Studies have also shown that TLN2 is a direct target of miR-132, which is epigenetically silenced in prostate cancer,[18] suggesting that talin-2 may play a role in modulating cell adhesion in prostate cancer. # Interactions TLN2 has been shown to interact with: - ACTA1,[19] - CD61,[20][21] - ITGB1,[22] - LAYN,[23][24] - PTK2,[25][26]

https://www.wikidoc.org/index.php/TLN2

abfa2c4c8e5ebd5f3cb429d4405389c0bf5ac2fd

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TLR2

TLR2 Toll-like receptor 2 also known as TLR2 is a protein that in humans is encoded by the TLR2 gene. TLR2 has also been designated as CD282 (cluster of differentiation 282). TLR2 is one of the toll-like receptors and plays a role in the immune system. TLR2 is a membrane protein, a receptor, which is expressed on the surface of certain cells and recognizes foreign substances and passes on appropriate signals to the cells of the immune system. # Function The protein encoded by this gene is a member of the Toll-like receptor (TLR) family, which plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. This gene is expressed most abundantly in peripheral blood leukocytes, and mediates host response to Gram-positive bacteria and yeast via stimulation of NF-κB. In the intestine, TLR2 regulates the expression of CYP1A1, which is a key enzyme in detoxication of carcinogenic polycyclic aromatic hydrocarbons such as benzo(a)pyrene. # Background The immune system recognizes foreign pathogens and eliminates them. This occurs in several phases. In the early inflammation phase, the pathogens are recognized by antibodies that are already present (innate or acquired through prior infection; see also cross-reactivity). Immune-system components (e.g. complement) are bound to the antibodies and kept near, in reserve to disable them via phagocytosis by scavenger cells (e.g. macrophages). Dendritic cells are likewise capable of phagocytizing but do not do it for the purpose of direct pathogen elimination. Rather, they infiltrate the spleen and lymph nodes, and each presents components of an antigen there, as the result of which specific antibodies are formed that recognize precisely that antigen. These newly formed antibodies would arrive too late in an acute infection, however, so what we think of as "immunology" constitutes only the second half of the process. Because this phase would always start too late to play an essential role in the defense process, a faster-acting principle is applied ahead of it, one that occurs only in forms of life that are phylogenetically more highly developed. What are called pattern-recognition receptors come into play here. This refers to receptors that recognize the gross, primarily structural features of molecules not innate to the host organism. These include, for example, lipids with a totally different basic chemical structure. Such receptors are bound directly to cells of the immune system and cause immediate activation of their respective nonspecific immune cells. A prime example of such a foreign ligand is bacterial endotoxin, whose effects have been known for generations. When it enters the bloodstream it causes systematic activation of the early-phase response, with all the side effects of septic shock. This is known in the laboratory as the Shwartzman phenomenon. The intended effect is to mobilize the organism for combat, so to speak, and eliminate most of the pathogens. # Mechanism As a membrane surface receptor, TLR2 recognizes many bacterial, fungal, viral, and certain endogenous substances. In general, this results in the uptake (internalization, phagocytosis) of bound molecules by endosomes/phagosomes and in cellular activation; thus such elements of innate immunity as macrophages, PMNs and dendritic cells assume functions of nonspecific immune defense, B1a and MZ B cells form the first antibodies, and specific antibody formation gets started in the process. Cytokines participating in this include tumor necrosis factor-alpha (TNF-α) and various interleukins (IL-1α, IL-1β, IL-6, IL-8, IL-12). Before the TLRs were known, several of the substances mentioned were classified as modulins. Due to the cytokine pattern, which corresponds more closely to Th1, an immune deviation is seen in this direction in most experimental models, away from Th2 characteristics. Conjugates are being developed as vaccines or are already being used without a priori knowledge. A peculiarity first recognized in 2006 is the expression of TLR2 on Tregs (a type of T cell), which experience both TCR-controlled proliferation and functional inactivation. This leads to disinhibition of the early inflammation phase and of specific antibody formation. Following a reduction in pathogen count, many pathogen-specific Tregs are present that, now without a TLR2 signal, become active and inhibit the specific and inflammatory immune reactions (see also TNF-β, IL-10). Older literature that ascribes a direct immunity-stimulating effect via TLR2 to a given molecule must be interpreted in light of the fact that the TLR2 knockouts employed typically have very few Tregs. Functionally relevant polymorphisms are reported that cause functional impairment and thus, in general, reduced survival rates, in particular in infections/sepsis with Gram-positive bacteria. Signal transduction is depicted under Toll-like receptor. # Expression TLR2 is expressed on microglia, Schwann cells, monocytes, macrophages, dendritic cells, polymorphonuclear leukocytes (PMNs or PMLs), B cells (B1a, MZ B, B2), and T cells, including Tregs (CD4+CD25+ regulatory T cells). In some cases, it occurs in a heterodimer (combination molecule), e.g., paired with TLR-1 or TLR-6. TLR2 is also found in the epithelia of air passages, pulmonary alveoli, renal tubules, and the Bowman's capsules in renal corpuscles. TLR2 is also expressed by intestinal epithelial cells and subsets of lamina propria mononuclear cells in the gastrointestinal tract . In the skin, it is found on keratinocytes and sebaceous glands; spc1 is induced here, allowing a bactericidal sebum to be formed. # Agonists The following ligands have been reported to be agonists of the toll-like receptor 2: # Interactions ## Protein-protein interactions TLR 2 has been shown to interact with TLR 1 and TOLLIP. ## Protein-ligand interactions TLR2 resides on the plasma membrane where it responds to lipid-containing PAMPs such as lipoteichoic acid and di- and tri-acylated cysteine-containing lipopeptides. It does this by forming dimeric complexes with either TLR 1 or TLR6 on the plasma membrane. TLR2 interactions with malarial glycophosphatidylinositols of Plasmodium falciparum was shown and a detailed structure of TLR–GPI interactions was computationally predicted. # Gene polymorphisms Various single nucleotide polymorphisms (SNPs) of the TLR2 have been identified and for some of them an association with faster progression and a more severe course of sepsis in critically ill patients was reported. No association with occurrence of severe staphylococcal infection was found.

TLR2 Toll-like receptor 2 also known as TLR2 is a protein that in humans is encoded by the TLR2 gene.[1] TLR2 has also been designated as CD282 (cluster of differentiation 282). TLR2 is one of the toll-like receptors and plays a role in the immune system. TLR2 is a membrane protein, a receptor, which is expressed on the surface of certain cells and recognizes foreign substances and passes on appropriate signals to the cells of the immune system. # Function The protein encoded by this gene is a member of the Toll-like receptor (TLR) family, which plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. This gene is expressed most abundantly in peripheral blood leukocytes, and mediates host response to Gram-positive bacteria[2] and yeast via stimulation of NF-κB.[3] In the intestine, TLR2 regulates the expression of CYP1A1,[4] which is a key enzyme in detoxication of carcinogenic polycyclic aromatic hydrocarbons such as benzo(a)pyrene.[5] # Background The immune system recognizes foreign pathogens and eliminates them. This occurs in several phases. In the early inflammation phase, the pathogens are recognized by antibodies that are already present (innate or acquired through prior infection; see also cross-reactivity). Immune-system components (e.g. complement) are bound to the antibodies and kept near, in reserve to disable them via phagocytosis by scavenger cells (e.g. macrophages). Dendritic cells are likewise capable of phagocytizing but do not do it for the purpose of direct pathogen elimination. Rather, they infiltrate the spleen and lymph nodes, and each presents components of an antigen there, as the result of which specific antibodies are formed that recognize precisely that antigen. These newly formed antibodies would arrive too late in an acute infection, however, so what we think of as "immunology" constitutes only the second half of the process. Because this phase would always start too late to play an essential role in the defense process, a faster-acting principle is applied ahead of it, one that occurs only in forms of life that are phylogenetically more highly developed. What are called pattern-recognition receptors come into play here. This refers to receptors that recognize the gross, primarily structural features of molecules not innate to the host organism. These include, for example, lipids with a totally different basic chemical structure. Such receptors are bound directly to cells of the immune system and cause immediate activation of their respective nonspecific immune cells. A prime example of such a foreign ligand is bacterial endotoxin, whose effects have been known for generations. When it enters the bloodstream it causes systematic activation of the early-phase response, with all the side effects of septic shock. This is known in the laboratory as the Shwartzman phenomenon. The intended effect is to mobilize the organism for combat, so to speak, and eliminate most of the pathogens. # Mechanism As a membrane surface receptor, TLR2 recognizes many bacterial, fungal, viral, and certain endogenous substances. In general, this results in the uptake (internalization, phagocytosis) of bound molecules by endosomes/phagosomes and in cellular activation; thus such elements of innate immunity as macrophages, PMNs and dendritic cells assume functions of nonspecific immune defense, B1a and MZ B cells form the first antibodies, and specific antibody formation gets started in the process. Cytokines participating in this include tumor necrosis factor-alpha (TNF-α) and various interleukins (IL-1α, IL-1β, IL-6, IL-8, IL-12). Before the TLRs were known, several of the substances mentioned were classified as modulins. Due to the cytokine pattern, which corresponds more closely to Th1, an immune deviation is seen in this direction in most experimental models, away from Th2 characteristics. Conjugates are being developed as vaccines or are already being used without a priori knowledge. A peculiarity first recognized in 2006 is the expression of TLR2 on Tregs (a type of T cell), which experience both TCR-controlled proliferation and functional inactivation. This leads to disinhibition of the early inflammation phase and of specific antibody formation. Following a reduction in pathogen count, many pathogen-specific Tregs are present that, now without a TLR2 signal, become active and inhibit the specific and inflammatory immune reactions (see also TNF-β, IL-10). Older literature that ascribes a direct immunity-stimulating effect via TLR2 to a given molecule must be interpreted in light of the fact that the TLR2 knockouts employed typically have very few Tregs. Functionally relevant polymorphisms are reported that cause functional impairment and thus, in general, reduced survival rates, in particular in infections/sepsis with Gram-positive bacteria. Signal transduction is depicted under Toll-like receptor. # Expression TLR2 is expressed on microglia, Schwann cells, monocytes, macrophages, dendritic cells, polymorphonuclear leukocytes (PMNs or PMLs), B cells (B1a, MZ B, B2), and T cells, including Tregs (CD4+CD25+ regulatory T cells). In some cases, it occurs in a heterodimer (combination molecule), e.g., paired with TLR-1 or TLR-6. TLR2 is also found in the epithelia of air passages, pulmonary alveoli, renal tubules, and the Bowman's capsules in renal corpuscles. TLR2 is also expressed by intestinal epithelial cells and subsets of lamina propria mononuclear cells in the gastrointestinal tract [6] . In the skin, it is found on keratinocytes and sebaceous glands; spc1 is induced here, allowing a bactericidal sebum to be formed. # Agonists The following ligands have been reported to be agonists of the toll-like receptor 2: # Interactions ## Protein-protein interactions TLR 2 has been shown to interact with TLR 1[8] and TOLLIP.[9] ## Protein-ligand interactions TLR2 resides on the plasma membrane where it responds to lipid-containing PAMPs such as lipoteichoic acid and di- and tri-acylated cysteine-containing lipopeptides. It does this by forming dimeric complexes with either TLR 1 or TLR6 on the plasma membrane.[10] TLR2 interactions with malarial glycophosphatidylinositols of Plasmodium falciparum was shown[11] and a detailed structure of TLR–GPI interactions was computationally predicted.[12] # Gene polymorphisms Various single nucleotide polymorphisms (SNPs) of the TLR2 have been identified [13] and for some of them an association with faster progression and a more severe course of sepsis in critically ill patients was reported.[14] No association with occurrence of severe staphylococcal infection was found.[15]

https://www.wikidoc.org/index.php/TLR2

57f674250a72e00f4c74bd1407f88cb9f8e1078b

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TLR3

TLR3 Toll-like receptor 3 (TLR3) also known as CD283 (cluster of differentiation 283) is a protein that in humans is encoded by the TLR3 gene. TLR3 is a member of the toll-like receptor family of pattern recognition receptors of the innate immune system. # Function TLR3 is a member of the toll-like receptor (TLR) family which plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. This receptor is most abundantly expressed in placenta and pancreas, and is restricted to the dendritic subpopulation of the leukocytes. It recognizes dsRNA associated with viral infection, and induces the activation of IRF3 and NF-κB. Unlike other TLRs, TLR3 uses TRIF as the sole adaptor. IRF3 ultimately induces the production of type I interferons. It may thus play a role in host defense against viruses. TLR3 recognizes double-stranded RNA, a form of genetic information carried by some viruses such as reoviruses. Additionally, an ephemeral form of double-stranded RNA exists as a replicative intermediate during virus replication. Upon recognition, TLR 3 induces the activation of IRF3 to increase production of type I interferons which signal other cells to increase their antiviral defenses. Double-stranded RNA is also recognised by the cytoplasmic receptors RIG-I and MDA-5. TLR3 displays a protective role in mouse models of atherosclerosis, and activation of TLR3 signaling is associated with ischemic preconditioning-induced protection against brain ischemia and attenuation of reactive astrogliosis. Furthermore, TLR3 activation has been shown to promote hair follicle regeneration in skin wound healing. In addition, TLR3 activators show effects on human vascular cells. # Structure The structure of TLR3 was reported in June 2005 by researchers at The Scripps Research Institute. TLR3 forms a large horseshoe shape that contacts with a neighboring horseshoe, forming a "dimer" of two horseshoes. Much of the TLR3 protein surface is covered with sugar molecules, making it a glycoprotein, but on one face (including the proposed interface between the two horseshoes), there is a large sugar-free surface. This surface also contains two distinct patches rich in positively charged amino acids, which may be a binding site for negatively charged double-stranded RNA. Despite being a glycoprotein, TLR3 crystallises readily – a prerequisite for structural analysis by x-ray crystallography.

TLR3 Toll-like receptor 3 (TLR3) also known as CD283 (cluster of differentiation 283) is a protein that in humans is encoded by the TLR3 gene.[1] TLR3 is a member of the toll-like receptor family of pattern recognition receptors of the innate immune system. # Function TLR3 is a member of the toll-like receptor (TLR) family which plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. This receptor is most abundantly expressed in placenta and pancreas, and is restricted to the dendritic subpopulation of the leukocytes. It recognizes dsRNA associated with viral infection, and induces the activation of IRF3 and NF-κB.[2] Unlike other TLRs, TLR3 uses TRIF as the sole adaptor.[2] IRF3 ultimately induces the production of type I interferons. It may thus play a role in host defense against viruses.[3] TLR3 recognizes double-stranded RNA, a form of genetic information carried by some viruses such as reoviruses. Additionally, an ephemeral form of double-stranded RNA exists as a replicative intermediate during virus replication.[4] Upon recognition, TLR 3 induces the activation of IRF3 to increase production of type I interferons which signal other cells to increase their antiviral defenses. Double-stranded RNA is also recognised by the cytoplasmic receptors RIG-I and MDA-5.[5] TLR3 displays a protective role in mouse models of atherosclerosis,[6] and activation of TLR3 signaling is associated with ischemic preconditioning-induced protection against brain ischemia and attenuation of reactive astrogliosis.[7][8] Furthermore, TLR3 activation has been shown to promote hair follicle regeneration in skin wound healing.[9] In addition, TLR3 activators show effects on human vascular cells.[6] # Structure The structure of TLR3 was reported in June 2005 by researchers at The Scripps Research Institute.[10] TLR3 forms a large horseshoe shape that contacts with a neighboring horseshoe, forming a "dimer" of two horseshoes. Much of the TLR3 protein surface is covered with sugar molecules, making it a glycoprotein, but on one face (including the proposed interface between the two horseshoes), there is a large sugar-free surface. This surface also contains two distinct patches rich in positively charged amino acids, which may be a binding site for negatively charged double-stranded RNA. Despite being a glycoprotein, TLR3 crystallises readily – a prerequisite for structural analysis by x-ray crystallography.

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TLR4

TLR4 Toll-like receptor 4 is a protein that in humans is encoded by the TLR4 gene. TLR4 is a transmembrane protein, member of the toll-like receptor family, which belongs to the pattern recognition receptor (PRR) family. Its activation leads to an intracellular signaling pathway NF-κB and inflammatory cytokine production which is responsible for activating the innate immune system. It is most well-known for recognizing lipopolysaccharide (LPS), a component present in many Gram-negative bacteria (e.g. Neisseria spp.) and select Gram-positive bacteria. Its ligands also include several viral proteins, polysaccharide, and a variety of endogenous proteins such as low-density lipoprotein, beta-defensins, and heat shock protein. TLR4 has also been designated as CD284 (cluster of differentiation 284). The molecular weight of TLR4 is approximately 95 kDa. # Function The protein encoded by this gene is a member of the toll-like receptor (TLR) family, which plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. This receptor is most abundantly expressed in placenta, and in myelomonocytic subpopulation of the leukocytes. It cooperates with LY96 (also referred as MD-2) and CD14 to mediate in signal transduction events induced by lipopolysaccharide (LPS) found in most gram-negative bacteria. Mutations in this gene have been associated with differences in LPS responsiveness. TLR4 signaling responds to signals by forming a complex using an extracellular leucine-rich repeat domain (LRR) and an intracellular toll/interleukin-1 receptor (TIR) domain. LPS stimulation induces a series of interactions with several accessory proteins which form the TLR4 complex on the cell surface. LPS recognition is initiated by an LPS binding to an LBP protein. This LPS-LBP complex transfers the LPS to CD14. CD14 is a glycosylphosphatidylinositol-anchored membrane protein that binds the LPS-LBP complex and facilitates the transfer of LPS to MD-2 protein, which is associated with the extracellular domain of TLR4. LPS binding promotes the dimerization of TLR4/MD-2. The conformational changes of the TLR4 induce the recruitment of intracellular adaptor proteins containing the TIR domain which is necessary to activate the downstream signaling pathway. Several transcript variants of this gene have been found, but the protein-coding potential of most of them is uncertain. Most of the reported effects of TLR4 signaling in tumors are pro-carcinogenic mainly due to contributions of proinflammatory cytokine signaling (whose expression is driven by TLR-mediated signals) to tumor-promoting microenvironment. # Signaling Upon LPS recognition, conformational changes in the TLR4 receptors result in recruitment of intracellular TIR-domains containing adaptor molecules. These adaptors are associated with the TLR4 cluster via homophilic interactions between the TIR domains. There are four adaptor proteins involved in two major intracellular signaling pathways. ## MyD88 – Dependent Pathway The MyD88-dependent pathway is regulated by two adaptor-associated proteins: Myeloid Differentiation Primary Response Gene 88 (MyD88) and TIR Domain-Containing Adaptor Protein (TIRAP). TIRAP-MyD88 regulates early NF-κβ activation and production of proinflammatory cytokines, such as IL-12. MyD88 signaling involves the activation of IL-1 Receptor-Associated Kinases (IRAKs) and the adaptor molecules TNF Receptor-Associated Factor 6 (TRAF6). TRAF6 induces the activation of TAK1 (Transforming growth factor-β-Activated Kinase 1) that leads to the activation of MAPK cascades (Mitogen-Activated Protein Kinase) and IKK (IκB Kinase). IKKs' signaling pathway leads to the induction of the transcription factor NF-κB, while activation of MAPK cascades lead to the activation of another transcription factor AP-1. Both of them have a role in the expression of proinflammatory cytokines. The activation of NF-κB via TAK-1 is complex, and it starts by the assembly of a protein complex called the signalosome, which is made of a scaffolding protein, called NEMO. The protein complex is made from two different κB kinases, called IKKα and IKKβ. This causes the addition of a small regulatory protein to the signalosome called ubiquitin, that acts to initiate the release of the NF-κB protein, which coordinates translocation in the nucleus of cytokines. ## MyD88 – Independent Pathway This TRIF-dependent pathway involves the recruitment of the adaptor proteins TIR-domain-containing adaptor inducing interferon-β (TRIF) and TRIF-related Adaptor Molecule (TRAM). TRAM-TRIF signals activate the transcription factor Interferon Regulatory Factor-3 (IRF3) via TRAF3. IRF3 activation induces the production of type 1 interferons. ## SARM: Negative Regulator of the TRIF-mediated Pathway A fifth TIR-domain-containing adaptor protein called Sterile α and HEAT (Armadillo motif) (SARM) is a TLR4 signaling pathway inhibitor. SARM activation by LPS-binding inhibits -TRIF-mediated pathways but does not inhibit MyD88-mediated pathways. This mechanism prevents an excessive activation in response to LPS which may lead to inflammation-induced damage such as sepsis. # Evolutionary history TLR4 originated when TLR2 and TLR4 diverged about 500 million years ago near the beginning of vertebrate evolution. Sequence alignments of human and great ape TLR4 exons have demonstrated that not much evolution has occurred in human TLR4 since our divergence from our last common ancestor with chimpanzees; human and chimp TLR4 exons only differ by three substitutions while humans and baboons are 93.5% similar in the extracellular domain. Notably, humans possess a greater number of early stop codons in TLR4 than great apes; in a study of 158 humans worldwide, 0.6% had a nonsense mutation. This suggests that there are weaker evolutionary pressures on the human TLR4 than on our primate relatives. The distribution of human TLR4 polymorphisms matches the out-of-Africa migration, and it is likely that the polymorphisms were generated in Africa before migration to other continents. # Interactions TLR4 has been shown to interact with: - Lymphocyte antigen 96, - Myd88, and - TOLLIP. - Nickel, Intracellular trafficking of TLR4 is dependent on the GTPase Rab-11a, and knock down of Rab-11a results in hampered TLR4 recruitment to E. coli-containing phagosomes and subsequent reduced signal transduction through the MyD88-independent pathway. # Clinical significance Various single nucleotide polymorphisms (SNPs) of the TLR4 in humans have been identified and for some of them an association with increased susceptibility to Gram-negative bacterial infections or faster progression and a more severe course of sepsis in critically ill patients was reported. ## In insulin resistance Fetuin-A facilitates the binding of lipids to receptors, thereby inducing insulin resistance. ## In cancer progression TLR4 expression can be detected on many tumor cells and cell lines. TLR4 is capable of activating MAPK and NF-κB pathways, implicating possible direct role of cell-autonomous TLR4 signaling in regulation of carcinogenesis, in particular, through increased proliferation of tumor cells, apoptosis inhibition and metastasis. TLR4 signaling may also contribute to resistance to paclitaxel chemotherapy in ovary cancer and siRNA therapy in prostate cancer. 63% of breast cancer patients were reported to express TLR4 on tumor cells and the level of expression inversely correlated with the survival. Additionally, low MyD88 expression correlated with decreased metastasis to the lung and decreased CCL2 and CCL5 expression. TLR4 expression levels were the highest among TLRs in human breast cancer cell line MDA-MB-231 and TLR4 knockdown resulted in decreased proliferation and decreased IL-6 and IL-8 levels. On the other hand, TLR4 signaling in immune and inflammatory cells of tumor microenvironment may lead to production of proinflammatory cytokines (TNF, IL-1β, IL-6, IL-18, etc.), immunosuppressive cytokines (IL-10, TGF-β, etc.) and angiogenic mediators (VEGF, EGF, TGF-β, etc.). These activities may result in further polarization of tumor-associated macrophages, conversion of fibroblasts into tumor-promoting cancer-associated fibroblasts, conversion of dendritic cells into tumor-associated DCs and activation of pro-tumorigenic functions of immature myeloid cells - Myeloid-derived Suppressor Cells (MDSC). TLR signaling has been linked to accumulation and function of MDSC at the site of tumor and it also allows mesenchymal stromal cells to counter NK cell-mediated anti-tumor immunity. In HepG2 hepatoblastoma cells LPS increased TLR4 levels, cell proliferation and resistance to chemotherapy, and these phenomena could be reversed by TLR4 gene knockdown. Similarly, LPS stimulation of human liver cancer cell line H7402 resulted in TLR4 upregulation, NF-κB activation, TNF, IL-6 and IL-8 production and increased proliferation that could be reversed by signal transducer and STAT3 inhibition.Besides the well known successful usage of Bacillus Calmette–Guérin (BCG) in the therapy of bladder cancer there are reports on the treatment of oral squamous cell carcinoma, gastric cancer and cervical cancer with lyophilized streptococcal preparation OK-432 and utilization of TLR4/TLR2 ligands – derivatives of muramyl dipeptide. ## In pregnancy Activation of TLR4 in intrauterine infections leads to deregulation of prostaglandin synthesis, leading to uterine smooth muscle contraction. ## Asp299Gly polymorphism Classically, TLR4 is said to be the receptor for LPS, however TLR4 has also been shown to be activated by other kinds of lipids. Plasmodium falciparum, a parasite known to cause the most common and serious form of malaria that is seen primarily in Africa, produces glycosylphosphatidylinositol, which can activate TLR4. Two SNPs in TLR4 are co-expressed with high penetrance in African populations (i.e. TLR-4-Asp299Gly and TLR-4-Thr399Ile). These Polymorphisms are associated with an increase in TLR4-Mediated IL-10 production—an immunomodulator—and a decrease in proinflammatory cytokines. The TLR-4-Asp299Gly point mutation is strongly correlated with an increased infection rate with Plasmodium falciparum. It appears that the mutation prevents TLR4 from acting as vigorously against, at least some plasmodial infections. The malaria infection rate and associated morbidity are higher in TLR-4-Asp299Gly group, but mortality appears to be decreased. This may indicate that at least part of the pathogenesis of malaria takes advantage of cytokine production. By reducing the cytokine production via the TLR4 mutation, the infection rate may increase, but the number of deaths due to the infection seem to decrease. In addition, TLR4-D299G has been associated with aggressive colorectal cancer in humans. It has been shown that human colon adenocarcinomas from patients with TLR4-D299G were more frequently of an advanced stage with metastasis than those with wild-type TLR4. The same study demonstrated functionally that intestinal epithelial cells (Caco-2) expressing TLR4-D299G underwent epithelial-mesenchymal transition and morphologic changes associated with tumor progression, whereas intestinal epithelial cells expressing wild-type TLR4 did not. # Animal studies A link between the TLR4 receptor and binge drinking has been suggested. When genes responsible for the expression of TLR4 and GABA receptors are manipulated in rodents that had been bred and trained to drink excessively, the animals showed a "profound reduction" in drinking behaviours. Additionally, it has been shown that ethanol, even in the absence of LPS, can activate TLR4 signaling pathways. High levels of TLR4 molecules and M2 tumor-associated macrophages are associated with increased susceptibility to cancer growth in mice deprived of sleep. Mice genetically modified so that they could not produce TLR4 molecules showed normal cancer growth. # Drugs targeting TLR4 Toll-like receptor 4 has been shown to be important for the long-term side-effects of opioid analgesic drugs. Various μ-opioid receptor ligands have been tested and found to also possess action as agonists or antagonists of TLR4, with opioid agonists such as morphine being TLR4 agonists, while opioid antagonists such as naloxone were found to be TLR4 antagonists. Activation of TLR4 leads to downstream release of inflammatory modulators including TNF-α and Interleukin-1, and constant low-level release of these modulators is thought to reduce the efficacy of opioid drug treatment with time, and be involved in both the development of tolerance to opioid analgesic drugs, and in the emergence of side-effects such as hyperalgesia and allodynia that can become a problem following extended use of opioid drugs. Drugs that block the action of TNF-α or IL-1β have been shown to increase the analgesic effects of opioids and reduce the development of tolerance and other side-effects, and this has also been demonstrated with drugs that block TLR4 itself. The response of TLR4 to opioid drugs has been found to be enantiomer-independent, so the "unnatural" enantiomers of opioid drugs such as morphine and naloxone, which lack affinity for opioid receptors, still produce the same activity at TLR4 as their "normal" enantiomers. This means that the unnatural enantiomers of opioid antagonists, such as (+)-naloxone, can be used to block the TLR4 activity of opioid analgesic drugs, while leaving the μ-opioid receptor mediated analgesic activity unaffected.) This may also be the mechanism behind the beneficial effect of ultra-low dose naltrexone on opioid analgesia. Morphine causes inflammation by binding to the protein lymphocyte antigen 96, which, in turn, causes the protein to bind to Toll-like receptor 4 (TLR4). The morphine-induced TLR4 activation attenuates pain suppression by opioids and enhances the development of opioid tolerance and addiction, drug abuse, and other negative side effects such as respiratory depression and hyperalgesia. Drug candidates that target TLR4 may improve opioid-based pain management therapies. ## Agonists - Buprenorphine - Carbamazepine - Ethanol - Fentanyl - Levorphanol - Lipopolysaccharides (LPS) - Methadone - Morphine - Oxcarbazepine - Oxycodone - Pethidine - Glucuronoxylomannan from Cryptococcus - Morphine-3-glucuronide (inactive at opioid receptors, so selective for TLR4 activation) - Tapentadol (mixed agonist/antagonist) - "Unnatural" isomers such as (+)-morphine activate TLR4 but lack opioid receptor activity, although (+)-morphine also shows activity as a sigma receptor agonist. ## Antagonists - The lipid A analog eritoran acts as a TLR4 antagonist. As of December 2009, it was being developed as a drug against severe sepsis. However, in 2013, a news story said the results against sepsis were somewhat disappointing and that it was better used to treat certain cases of severe influenza. Although it does not treat the virus itself, it could be used against the massive immune reaction called cytokine storm which often occurs later in the infection and is a major cause of mortality from severe influenza. - Amitriptyline - Cyclobenzaprine - Ketotifen - Imipramine - Mianserin - Ibudilast - Pinocembrin - Naloxone - Naltrexone - (+)-naltrexone - LPS-RS - Propentofylline - Tapentadol (mixed agonist/antagonist) - (+)-naloxone ("unnatural" isomer, lacks opioid receptor affinity so selective for TLR4 inhibition)

TLR4 Toll-like receptor 4 is a protein that in humans is encoded by the TLR4 gene. TLR4 is a transmembrane protein, member of the toll-like receptor family, which belongs to the pattern recognition receptor (PRR) family. Its activation leads to an intracellular signaling pathway NF-κB and inflammatory cytokine production which is responsible for activating the innate immune system.[1] It is most well-known for recognizing lipopolysaccharide (LPS), a component present in many Gram-negative bacteria (e.g. Neisseria spp.) and select Gram-positive bacteria. Its ligands also include several viral proteins, polysaccharide, and a variety of endogenous proteins such as low-density lipoprotein, beta-defensins, and heat shock protein.[2] TLR4 has also been designated as CD284 (cluster of differentiation 284). The molecular weight of TLR4 is approximately 95 kDa. # Function The protein encoded by this gene is a member of the toll-like receptor (TLR) family, which plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. This receptor is most abundantly expressed in placenta, and in myelomonocytic subpopulation of the leukocytes. It cooperates with LY96 (also referred as MD-2) and CD14 to mediate in signal transduction events induced by lipopolysaccharide (LPS)[3] found in most gram-negative bacteria. Mutations in this gene have been associated with differences in LPS responsiveness. TLR4 signaling responds to signals by forming a complex using an extracellular leucine-rich repeat domain (LRR) and an intracellular toll/interleukin-1 receptor (TIR) domain. LPS stimulation induces a series of interactions with several accessory proteins which form the TLR4 complex on the cell surface. LPS recognition is initiated by an LPS binding to an LBP protein. This LPS-LBP complex transfers the LPS to CD14. CD14 is a glycosylphosphatidylinositol-anchored membrane protein that binds the LPS-LBP complex and facilitates the transfer of LPS to MD-2 protein, which is associated with the extracellular domain of TLR4. LPS binding promotes the dimerization of TLR4/MD-2. The conformational changes of the TLR4 induce the recruitment of intracellular adaptor proteins containing the TIR domain which is necessary to activate the downstream signaling pathway.[4] Several transcript variants of this gene have been found, but the protein-coding potential of most of them is uncertain.[5] Most of the reported effects of TLR4 signaling in tumors are pro-carcinogenic mainly due to contributions of proinflammatory cytokine signaling (whose expression is driven by TLR-mediated signals) to tumor-promoting microenvironment.[6] # Signaling Upon LPS recognition, conformational changes in the TLR4 receptors result in recruitment of intracellular TIR-domains containing adaptor molecules. These adaptors are associated with the TLR4 cluster via homophilic interactions between the TIR domains. There are four adaptor proteins involved in two major intracellular signaling pathways.[7] ## MyD88 – Dependent Pathway The MyD88-dependent pathway is regulated by two adaptor-associated proteins: Myeloid Differentiation Primary Response Gene 88 (MyD88) and TIR Domain-Containing Adaptor Protein (TIRAP). TIRAP-MyD88 regulates early NF-κβ activation and production of proinflammatory cytokines, such as IL-12.[1] MyD88 signaling involves the activation of IL-1 Receptor-Associated Kinases (IRAKs) and the adaptor molecules TNF Receptor-Associated Factor 6 (TRAF6). TRAF6 induces the activation of TAK1 (Transforming growth factor-β-Activated Kinase 1) that leads to the activation of MAPK cascades (Mitogen-Activated Protein Kinase) and IKK (IκB Kinase). IKKs' signaling pathway leads to the induction of the transcription factor NF-κB, while activation of MAPK cascades lead to the activation of another transcription factor AP-1. Both of them have a role in the expression of proinflammatory cytokines.[4] The activation of NF-κB via TAK-1 is complex, and it starts by the assembly of a protein complex called the signalosome, which is made of a scaffolding protein, called NEMO. The protein complex is made from two different κB kinases, called IKKα and IKKβ. This causes the addition of a small regulatory protein to the signalosome called ubiquitin, that acts to initiate the release of the NF-κB protein, which coordinates translocation in the nucleus of cytokines.[8] ## MyD88 – Independent Pathway This TRIF-dependent pathway involves the recruitment of the adaptor proteins TIR-domain-containing adaptor inducing interferon-β (TRIF) and TRIF-related Adaptor Molecule (TRAM). TRAM-TRIF signals activate the transcription factor Interferon Regulatory Factor-3 (IRF3) via TRAF3. IRF3 activation induces the production of type 1 interferons.[7] ## SARM: Negative Regulator of the TRIF-mediated Pathway A fifth TIR-domain-containing adaptor protein called Sterile α and HEAT (Armadillo motif) (SARM) is a TLR4 signaling pathway inhibitor. SARM activation by LPS-binding inhibits -TRIF-mediated pathways but does not inhibit MyD88-mediated pathways. This mechanism prevents an excessive activation in response to LPS which may lead to inflammation-induced damage such as sepsis.[4] # Evolutionary history TLR4 originated when TLR2 and TLR4 diverged about 500 million years ago near the beginning of vertebrate evolution.[9] Sequence alignments of human and great ape TLR4 exons have demonstrated that not much evolution has occurred in human TLR4 since our divergence from our last common ancestor with chimpanzees; human and chimp TLR4 exons only differ by three substitutions while humans and baboons are 93.5% similar in the extracellular domain.[10] Notably, humans possess a greater number of early stop codons in TLR4 than great apes; in a study of 158 humans worldwide, 0.6% had a nonsense mutation.[11][12] This suggests that there are weaker evolutionary pressures on the human TLR4 than on our primate relatives. The distribution of human TLR4 polymorphisms matches the out-of-Africa migration, and it is likely that the polymorphisms were generated in Africa before migration to other continents.[12][13] # Interactions TLR4 has been shown to interact with: - Lymphocyte antigen 96,[14][15] - Myd88,[16][17][18][19] and - TOLLIP.[20] - Nickel, [21] Intracellular trafficking of TLR4 is dependent on the GTPase Rab-11a, and knock down of Rab-11a results in hampered TLR4 recruitment to E. coli-containing phagosomes and subsequent reduced signal transduction through the MyD88-independent pathway.[22] # Clinical significance Various single nucleotide polymorphisms (SNPs) of the TLR4 in humans have been identified[23] and for some of them an association with increased susceptibility to Gram-negative bacterial infections [24] or faster progression and a more severe course of sepsis in critically ill patients was reported.[25] ## In insulin resistance Fetuin-A facilitates the binding of lipids to receptors, thereby inducing insulin resistance.[26] ## In cancer progression TLR4 expression can be detected on many tumor cells and cell lines. TLR4 is capable of activating MAPK and NF-κB pathways, implicating possible direct role of cell-autonomous TLR4 signaling in regulation of carcinogenesis, in particular, through increased proliferation of tumor cells, apoptosis inhibition and metastasis. TLR4 signaling may also contribute to resistance to paclitaxel chemotherapy in ovary cancer and siRNA therapy in prostate cancer. 63% of breast cancer patients were reported to express TLR4 on tumor cells and the level of expression inversely correlated with the survival. Additionally, low MyD88 expression correlated with decreased metastasis to the lung and decreased CCL2 and CCL5 expression. TLR4 expression levels were the highest among TLRs in human breast cancer cell line MDA-MB-231 and TLR4 knockdown resulted in decreased proliferation and decreased IL-6 and IL-8 levels. On the other hand, TLR4 signaling in immune and inflammatory cells of tumor microenvironment may lead to production of proinflammatory cytokines (TNF, IL-1β, IL-6, IL-18, etc.), immunosuppressive cytokines (IL-10, TGF-β, etc.) and angiogenic mediators (VEGF, EGF, TGF-β, etc.). These activities may result in further polarization of tumor-associated macrophages, conversion of fibroblasts into tumor-promoting cancer-associated fibroblasts, conversion of dendritic cells into tumor-associated DCs and activation of pro-tumorigenic functions of immature myeloid cells - Myeloid-derived Suppressor Cells (MDSC). TLR signaling has been linked to accumulation and function of MDSC at the site of tumor and it also allows mesenchymal stromal cells to counter NK cell-mediated anti-tumor immunity. In HepG2 hepatoblastoma cells LPS increased TLR4 levels, cell proliferation and resistance to chemotherapy, and these phenomena could be reversed by TLR4 gene knockdown. Similarly, LPS stimulation of human liver cancer cell line H7402 resulted in TLR4 upregulation, NF-κB activation, TNF, IL-6 and IL-8 production and increased proliferation that could be reversed by signal transducer and STAT3 inhibition.Besides the well known successful usage of Bacillus Calmette–Guérin (BCG) in the therapy of bladder cancer there are reports on the treatment of oral squamous cell carcinoma, gastric cancer and cervical cancer with lyophilized streptococcal preparation OK-432 and utilization of TLR4/TLR2 ligands – derivatives of muramyl dipeptide.[6] ## In pregnancy Activation of TLR4 in intrauterine infections leads to deregulation of prostaglandin synthesis, leading to uterine smooth muscle contraction. ## Asp299Gly polymorphism Classically, TLR4 is said to be the receptor for LPS, however TLR4 has also been shown to be activated by other kinds of lipids. Plasmodium falciparum, a parasite known to cause the most common and serious form of malaria that is seen primarily in Africa, produces glycosylphosphatidylinositol, which can activate TLR4.[27] Two SNPs in TLR4 are co-expressed with high penetrance in African populations (i.e. TLR-4-Asp299Gly and TLR-4-Thr399Ile). These Polymorphisms are associated with an increase in TLR4-Mediated IL-10 production—an immunomodulator—and a decrease in proinflammatory cytokines.[28] The TLR-4-Asp299Gly point mutation is strongly correlated with an increased infection rate with Plasmodium falciparum. It appears that the mutation prevents TLR4 from acting as vigorously against, at least some plasmodial infections. The malaria infection rate and associated morbidity are higher in TLR-4-Asp299Gly group, but mortality appears to be decreased. This may indicate that at least part of the pathogenesis of malaria takes advantage of cytokine production. By reducing the cytokine production via the TLR4 mutation, the infection rate may increase, but the number of deaths due to the infection seem to decrease.[27] In addition, TLR4-D299G has been associated with aggressive colorectal cancer in humans. It has been shown that human colon adenocarcinomas from patients with TLR4-D299G were more frequently of an advanced stage with metastasis than those with wild-type TLR4. The same study demonstrated functionally that intestinal epithelial cells (Caco-2) expressing TLR4-D299G underwent epithelial-mesenchymal transition and morphologic changes associated with tumor progression, whereas intestinal epithelial cells expressing wild-type TLR4 did not.[29] # Animal studies A link between the TLR4 receptor and binge drinking has been suggested. When genes responsible for the expression of TLR4 and GABA receptors are manipulated in rodents that had been bred and trained to drink excessively, the animals showed a "profound reduction" in drinking behaviours.[30] Additionally, it has been shown that ethanol, even in the absence of LPS, can activate TLR4 signaling pathways.[31] High levels of TLR4 molecules and M2 tumor-associated macrophages are associated with increased susceptibility to cancer growth in mice deprived of sleep. Mice genetically modified so that they could not produce TLR4 molecules showed normal cancer growth.[32] # Drugs targeting TLR4 Toll-like receptor 4 has been shown to be important for the long-term side-effects of opioid analgesic drugs. Various μ-opioid receptor ligands have been tested and found to also possess action as agonists or antagonists of TLR4, with opioid agonists such as morphine being TLR4 agonists, while opioid antagonists such as naloxone were found to be TLR4 antagonists. Activation of TLR4 leads to downstream release of inflammatory modulators including TNF-α and Interleukin-1, and constant low-level release of these modulators is thought to reduce the efficacy of opioid drug treatment with time, and be involved in both the development of tolerance to opioid analgesic drugs,[33][34] and in the emergence of side-effects such as hyperalgesia and allodynia that can become a problem following extended use of opioid drugs.[35][36] Drugs that block the action of TNF-α or IL-1β have been shown to increase the analgesic effects of opioids and reduce the development of tolerance and other side-effects,[37][38] and this has also been demonstrated with drugs that block TLR4 itself. The response of TLR4 to opioid drugs has been found to be enantiomer-independent, so the "unnatural" enantiomers of opioid drugs such as morphine and naloxone, which lack affinity for opioid receptors, still produce the same activity at TLR4 as their "normal" enantiomers.[39][40] This means that the unnatural enantiomers of opioid antagonists, such as (+)-naloxone, can be used to block the TLR4 activity of opioid analgesic drugs, while leaving the μ-opioid receptor mediated analgesic activity unaffected.[41])[40][42] This may also be the mechanism behind the beneficial effect of ultra-low dose naltrexone on opioid analgesia.[43] Morphine causes inflammation by binding to the protein lymphocyte antigen 96, which, in turn, causes the protein to bind to Toll-like receptor 4 (TLR4).[44] The morphine-induced TLR4 activation attenuates pain suppression by opioids and enhances the development of opioid tolerance and addiction, drug abuse, and other negative side effects such as respiratory depression and hyperalgesia. Drug candidates that target TLR4 may improve opioid-based pain management therapies.[45] ## Agonists - Buprenorphine[46] - Carbamazepine[47] - Ethanol[48] - Fentanyl[46] - Levorphanol[46] - Lipopolysaccharides (LPS)[49] - Methadone[46] - Morphine[46] - Oxcarbazepine[47] - Oxycodone[46] - Pethidine[46] - Glucuronoxylomannan from Cryptococcus[50][51] - Morphine-3-glucuronide (inactive at opioid receptors, so selective for TLR4 activation)[36][46] - Tapentadol (mixed agonist/antagonist) - "Unnatural" isomers such as (+)-morphine activate TLR4 but lack opioid receptor activity,[39] although (+)-morphine also shows activity as a sigma receptor agonist.[52] ## Antagonists - The lipid A analog eritoran acts as a TLR4 antagonist. As of December 2009[update], it was being developed as a drug against severe sepsis.[53] However, in 2013, a news story said the results against sepsis were somewhat disappointing and that it was better used to treat certain cases of severe influenza. Although it does not treat the virus itself, it could be used against the massive immune reaction called cytokine storm which often occurs later in the infection and is a major cause of mortality from severe influenza.[54] - Amitriptyline[47] - Cyclobenzaprine[47] - Ketotifen[47] - Imipramine[47] - Mianserin[47] - Ibudilast[55] - Pinocembrin[56] - Naloxone[46] - Naltrexone[46] - (+)-naltrexone[46] - LPS-RS[46] - Propentofylline[citation needed] - Tapentadol (mixed agonist/antagonist) - (+)-naloxone ("unnatural" isomer, lacks opioid receptor affinity so selective for TLR4 inhibition)[40]

https://www.wikidoc.org/index.php/TLR4

7209f46e5f42c71dd0c24c8b80b3c841a6f72846

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TLR5

TLR5 Toll-like receptor 5, also known as TLR5, is a protein which in humans is encoded by the TLR5 gene. It is a member of the toll-like receptor (TLR) family. TLR5 is known to recognize bacterial flagellin from invading mobile bacteria. Its has been shown to be involved in the onset of many diseases, which includes Inflammatory bowel disease. Recent studies have also shown that malfunctioning of TLR5 is likely related to osteoclastogenesis and bone loss. Abnormal TLR5 functioning is related to the onset of gastric, cervical, endometrial and ovarian cancers. # Function The TLR family plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. TLR5 is expressed on both immune and non-immune cells. TLR5 recognizes bacterial flagellin, a principal component of bacterial flagella and a virulence factor. The activation of this receptor mobilizes the nuclear factor NF-κB and stimulates tumor necrosis factor-alpha production. TLR5 recognizes flagellin, which is the protein monomer that makes up the filament of bacterial flagella, found on nearly all motile bacteria. There are highly conserved regions in the flagellin protein among all bacteria, facilitating the recognition of flagellin by a germ-line encoded receptor such as TLR5. However, some Proteobacteria flagella have acquired mutations preventing their recognition by TLR5. # Signaling pathway and regulation The TLR5 signaling cascade is commonly triggered by the binding of bacterial flagellum to TLR5 on the cell surface. Binding of flagellum induces the dimerization of TLR5, which in turn recruits MyD88. The recruitment of MyD88 leads to subsequent activation of IRAK4, IRAK1, TRAF6, and eventually IκB kinases. Activation of IκB kinases contributes to the nuclear localization of NF-κB (a proinflammatory cytokine). NF-κB induces many downstream gene expressions, which initiates the canonical proinflammatory pathway. This TLR5/flagellum interaction results in different responses in difference cell types. In epithelial cells, binding of flagellum to TLR5 induces IL8 production. In human monocytes and dendritic cells, this interaction results in the secretion of proinflammatory cytokines such as TNF. Recent study has identified Caveolin-1 as a potential regulator of TLR5 expression. In contrast to the decreased TLR4 level in senescent cells, TLR5 expression maintains relative stable during the aging process, which is correlated with the high level of Caveolin-1 in aging cells. Data from Caveolin-1 knockout mice demonstrated that TLR5 expression significantly decreases in the absence of Caveolin-1 expression in aging cells. It is hypothesized that the Caveolin-1 directly interacts with TLR5 to stabilize it and hence increases the level of TLR5. # Clinical significance ## Inflammatory bowel disease TLR5 may play a role in inflammatory bowel disease (IBD). TLR5-deficient mice develop spontaneous colitis and metabolic syndrome which are associated with altered gut microbiota. Statistically significant lower levels of TLR5 expression have been found in patients exhibiting moderate to severe ulcerative colitis (UC). In these patients, lower TLR5 mRNA levels were found along with decreased immunoreactivity of TLR5 in the inflamed mucosa of UC patients. ## Osteoclastogenesis and bone loss Bone loss and osteoclastogenesis are induced by inflammation in infectious and autoimmune diseases. A recent study has identified TLR5 as a novel mediator in the process of inflammation-induced bone loss and osteoclastogenesis. Flagellin, which is a TLR5-activating ligand, is present in synovial fluid from patients with rheumatoid arthritis. Activation of TLR5 in these patients leads to subsequent activation of receptor activator of NF-kB ligand (RANKL). Activation of RANKL leads to increased expression of osteoclastic genes. Activation of these genes results in robust osteoclast formation and bone loss. This process is absent in TLR5 knockout mice model. ## Cancer ### Gastric cancer Chronic inflammation in GI tract has been known to increase the risk of gastric cancer, with H. pylori being one of the most common resources of infection. TLR5 is an essential factor in inducing inflammatory response to H. pylori infection. During infection, expression and ligation of TLR5 and TLR2 are required for the activation of proinflammatory cytokines such as NF-κB. However, TLR5 interaction with H. pylori only induces weak TLR5 activation. The inflammatory response induced by TLR5 during H. pylori is also considered to be possibly flagellin independent. This suggests that an unknown H. pylori factor is responsible for this response In addition to inflammation induction, TLR5 is also shown to enhance gastric cancer cell proliferation through a ERK-dependent pathway. This is supported by the increased level of TLR5 expression from normal gastric mucosa to gastric cancer cells. ### Cervical cancer TLR5 is suggested to be possibly involved in HPV induced inflammation and subsequent cervical neoplasia formation. TLR5 is generally absent in normal cervical squamous epithelium. However, a gradually increased level of TLR5 expression has been detected in low-grade cervical intraepithelial neoplasia (CIN), high grade CIN, and invasive cervical cancer. However, the exact mechanism of interaction between TLR5 and HPV is not known. ### Ovarian cancer It has been reported that TLR5 expression is detected in both ovarian epithelium and ovarian cancer cell lines but not in ovarian stroma, suggesting a possible role of TLR5 in inflammation induced ovarian cancer onset.

TLR5 Toll-like receptor 5, also known as TLR5, is a protein which in humans is encoded by the TLR5 gene.[1] It is a member of the toll-like receptor (TLR) family. TLR5 is known to recognize bacterial flagellin from invading mobile bacteria.[2] Its has been shown to be involved in the onset of many diseases, which includes Inflammatory bowel disease.[3] Recent studies have also shown that malfunctioning of TLR5 is likely related to osteoclastogenesis and bone loss.[4] Abnormal TLR5 functioning is related to the onset of gastric, cervical, endometrial and ovarian cancers.[5][6] # Function The TLR family plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. TLR5 is expressed on both immune and non-immune cells.[7] TLR5 recognizes bacterial flagellin, a principal component of bacterial flagella and a virulence factor. The activation of this receptor mobilizes the nuclear factor NF-κB and stimulates tumor necrosis factor-alpha production.[8] TLR5 recognizes flagellin,[9] which is the protein monomer that makes up the filament of bacterial flagella, found on nearly all motile bacteria. There are highly conserved regions in the flagellin protein among all bacteria, facilitating the recognition of flagellin by a germ-line encoded receptor such as TLR5.[10] However, some Proteobacteria flagella have acquired mutations preventing their recognition by TLR5.[11] # Signaling pathway and regulation The TLR5 signaling cascade is commonly triggered by the binding of bacterial flagellum to TLR5 on the cell surface. Binding of flagellum induces the dimerization of TLR5, which in turn recruits MyD88.[12] The recruitment of MyD88 leads to subsequent activation of IRAK4, IRAK1, TRAF6, and eventually IκB kinases.[13][14] Activation of IκB kinases contributes to the nuclear localization of NF-κB (a proinflammatory cytokine). NF-κB induces many downstream gene expressions, which initiates the canonical proinflammatory pathway. This TLR5/flagellum interaction results in different responses in difference cell types. In epithelial cells, binding of flagellum to TLR5 induces IL8 production. In human monocytes and dendritic cells, this interaction results in the secretion of proinflammatory cytokines such as TNF.[2] Recent study has identified Caveolin-1 as a potential regulator of TLR5 expression.[15] In contrast to the decreased TLR4 level in senescent cells, TLR5 expression maintains relative stable during the aging process, which is correlated with the high level of Caveolin-1 in aging cells. Data from Caveolin-1 knockout mice demonstrated that TLR5 expression significantly decreases in the absence of Caveolin-1 expression in aging cells.[15] It is hypothesized that the Caveolin-1 directly interacts with TLR5 to stabilize it and hence increases the level of TLR5. # Clinical significance ## Inflammatory bowel disease TLR5 may play a role in inflammatory bowel disease (IBD). TLR5-deficient mice develop spontaneous colitis [16] and metabolic syndrome which are associated with altered gut microbiota.[17] Statistically significant lower levels of TLR5 expression have been found in patients exhibiting moderate to severe ulcerative colitis (UC). In these patients, lower TLR5 mRNA levels were found along with decreased immunoreactivity of TLR5 in the inflamed mucosa of UC patients.[3] ## Osteoclastogenesis and bone loss Bone loss and osteoclastogenesis are induced by inflammation in infectious and autoimmune diseases.[4] A recent study has identified TLR5 as a novel mediator in the process of inflammation-induced bone loss and osteoclastogenesis. Flagellin, which is a TLR5-activating ligand, is present in synovial fluid from patients with rheumatoid arthritis. Activation of TLR5 in these patients leads to subsequent activation of receptor activator of NF-kB ligand (RANKL). Activation of RANKL leads to increased expression of osteoclastic genes. Activation of these genes results in robust osteoclast formation and bone loss.[4] This process is absent in TLR5 knockout mice model.[4] ## Cancer ### Gastric cancer Chronic inflammation in GI tract has been known to increase the risk of gastric cancer, with H. pylori being one of the most common resources of infection.[5] TLR5 is an essential factor in inducing inflammatory response to H. pylori infection. During infection, expression and ligation of TLR5 and TLR2 are required for the activation of proinflammatory cytokines such as NF-κB.[18] However, TLR5 interaction with H. pylori only induces weak TLR5 activation. The inflammatory response induced by TLR5 during H. pylori is also considered to be possibly flagellin independent. This suggests that an unknown H. pylori factor is responsible for this response[5] In addition to inflammation induction, TLR5 is also shown to enhance gastric cancer cell proliferation through a ERK-dependent pathway.[19] This is supported by the increased level of TLR5 expression from normal gastric mucosa to gastric cancer cells.[20] ### Cervical cancer TLR5 is suggested to be possibly involved in HPV induced inflammation and subsequent cervical neoplasia formation.[21] TLR5 is generally absent in normal cervical squamous epithelium. However, a gradually increased level of TLR5 expression has been detected in low-grade cervical intraepithelial neoplasia (CIN), high grade CIN, and invasive cervical cancer.[22] However, the exact mechanism of interaction between TLR5 and HPV is not known. ### Ovarian cancer It has been reported that TLR5 expression is detected in both ovarian epithelium and ovarian cancer cell lines but not in ovarian stroma, suggesting a possible role of TLR5 in inflammation induced ovarian cancer onset.[23]

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TLR7

TLR7 Toll-like receptor 7, also known as TLR7, is a protein that in humans is encoded by the TLR7 gene. Orthologs are found in mammals and birds. It is a member of the toll-like receptor (TLR) family and detects single stranded RNA. # Function The TLR family plays an important role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. This gene is predominantly expressed in lung, placenta, and spleen, and lies in close proximity to another family member, TLR8, on the human X chromosome. TLR7 recognizes single-stranded RNA in endosomes, which is a common feature of viral genomes which are internalised by macrophages and dendritic cells. TLR7 recognizes single-stranded RNA of viruses such as HIV and HCV,. TLR7 can recognize GU-rich single-stranded RNA. However, the presence of GU-rich sequences in the single-stranded RNA is not sufficient to stimulate TLR7. # Clinical significance Imiquimod acts upon TLR7. TLR7 has been shown to play a significant role in the pathogenesis of autoimmune disorders such as Systemic Lupus Erythematosus (SLE) as well as in the regulation of antiviral immunity. Although not yet fully elucidated, using an unbiased genome-scale screen with short hairpin RNA (shRNA), it has been demonstrated that the receptor TREML4 acts as an essential positive regulator of TLR7 signalling. In TREML4 -/- mice macrophages that are hyporesponsive to TLR7 agonists, macrophages fail to produce type I interferons due to impaired phosphorylation of the transcription factor STAT1 by the mitogen-activated protein kinase p38 and decreased recruitment of the adaptor MyD88 to TLR7. TREML4 deficiency reduced the production of inflammatory cytokines and autoantibodies in MRL/lpr mice, suggesting that TRL7 is a vital component of antiviral immunity and a predecessor factor in the pathogenesis of rheumatic diseases such as SLE. A TLR7 agonist, Aldara, an imidazoquinoline, has been approved for topical use in treating warts caused by papillomavirus and for actinic keratoses. Due to their ability to induce robust production of anti-cancer cytokines such as interleukin-12, TLR7 agonists have been investigated for cancer immunotherapy. Recent examples include TMX-202 delivery via liposomal formulation, as well as the delivery of resiquimod via nanoparticles formed from beta-cyclodextrin.

TLR7 Toll-like receptor 7, also known as TLR7, is a protein that in humans is encoded by the TLR7 gene. Orthologs are found in mammals and birds.[1] It is a member of the toll-like receptor (TLR) family and detects single stranded RNA. # Function The TLR family plays an important role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. This gene is predominantly expressed in lung, placenta, and spleen, and lies in close proximity to another family member, TLR8, on the human X chromosome.[2] TLR7 recognizes single-stranded RNA in endosomes, which is a common feature of viral genomes which are internalised by macrophages and dendritic cells. TLR7 recognizes single-stranded RNA of viruses such as HIV and HCV,.[3][4] TLR7 can recognize GU-rich single-stranded RNA.[3] However, the presence of GU-rich sequences in the single-stranded RNA is not sufficient to stimulate TLR7.[4] # Clinical significance Imiquimod acts upon TLR7.[5] TLR7 has been shown to play a significant role in the pathogenesis of autoimmune disorders such as Systemic Lupus Erythematosus (SLE) as well as in the regulation of antiviral immunity. Although not yet fully elucidated, using an unbiased genome-scale screen with short hairpin RNA (shRNA), it has been demonstrated that the receptor TREML4 acts as an essential positive regulator of TLR7 signalling. In TREML4 -/- mice macrophages that are hyporesponsive to TLR7 agonists, macrophages fail to produce type I interferons due to impaired phosphorylation of the transcription factor STAT1 by the mitogen-activated protein kinase p38 and decreased recruitment of the adaptor MyD88 to TLR7. TREML4 deficiency reduced the production of inflammatory cytokines and autoantibodies in MRL/lpr mice, suggesting that TRL7 is a vital component of antiviral immunity and a predecessor factor in the pathogenesis of rheumatic diseases such as SLE.[6] A TLR7 agonist, Aldara, an imidazoquinoline, has been approved for topical use in treating warts caused by papillomavirus and for actinic keratoses.[7] Due to their ability to induce robust production of anti-cancer cytokines such as interleukin-12, TLR7 agonists have been investigated for cancer immunotherapy. Recent examples include TMX-202 delivery via liposomal formulation,[8] as well as the delivery of resiquimod via nanoparticles formed from beta-cyclodextrin.[9]

https://www.wikidoc.org/index.php/TLR7

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TLR8

TLR8 Toll-like receptor 8 is a protein that in humans is encoded by the TLR8 gene. TLR8 has also been designated as CD288 (cluster of differentiation 288). It is a member of the toll-like receptor (TLR) family. # Function TLR8 seems to function differently in humans and mice. Until recently, TLR8 was believed to be nonfunctional in mice, but it seems to counteract TLR7 activity The TLR family plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. This gene is predominantly expressed in lung and peripheral blood leukocytes, and lies in close proximity to another family member, TLR7, on chromosome X. TLR8 can recognize GU-rich single-stranded RNA. However, the presence of GU-rich sequences in the single-stranded RNA is not sufficient to stimulate TLR8. TLR8 recognizes G-rich oligonucleotides. TLR8 is an endosomal receptor that recognizes single stranded RNA (ssRNA), and can recognize ssRNA viruses such as Influenza, Sendai, and Coxsackie B viruses. TLR8 binding to the viral RNA recruits MyD88 and leads to activation of the transcription factor NF-κB and an antiviral response. TLR8 recognizes single-stranded RNA of viruses such as HIV and HCV. # Clinical significance Genetic variants in TLR8 has recently been linked to susceptibility to pulmonary tuberculosis. ## As a drug target TLR8 agonists (e.g. VTX-2337) have undergone clinical trials as immune stimulants in combination therapy for some cancers.

TLR8 Toll-like receptor 8 is a protein that in humans is encoded by the TLR8 gene.[1] TLR8 has also been designated as CD288 (cluster of differentiation 288). It is a member of the toll-like receptor (TLR) family. # Function TLR8 seems to function differently in humans and mice. Until recently, TLR8 was believed to be nonfunctional in mice, but it seems to counteract TLR7 activity[2][3] The TLR family plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. This gene is predominantly expressed in lung and peripheral blood leukocytes, and lies in close proximity to another family member, TLR7, on chromosome X.[4] TLR8 can recognize GU-rich single-stranded RNA.[5] However, the presence of GU-rich sequences in the single-stranded RNA is not sufficient to stimulate TLR8.[6] TLR8 recognizes G-rich oligonucleotides.[7] TLR8 is an endosomal receptor that recognizes single stranded RNA (ssRNA), and can recognize ssRNA viruses such as Influenza, Sendai, and Coxsackie B viruses. TLR8 binding to the viral RNA recruits MyD88 and leads to activation of the transcription factor NF-κB and an antiviral response.[8] TLR8 recognizes single-stranded RNA of viruses such as HIV and HCV.[5][6] # Clinical significance Genetic variants in TLR8 has recently been linked to susceptibility to pulmonary tuberculosis.[9] ## As a drug target TLR8 agonists (e.g. VTX-2337) have undergone clinical trials as immune stimulants in combination therapy for some cancers.[10]

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TLR9

TLR9 Toll-like receptor 9 is a protein that in humans is encoded by the TLR9 gene. TLR9 has also been designated as CD289 (cluster of differentiation 289). It is a member of the toll-like receptor (TLR) family. TLR9 is an important receptor expressed in immune system cells including dendritic cells, macrophages, natural killer cells, and other antigen presenting cells. TLR9 preferentially binds DNA present in bacteria and viruses, and triggers signaling cascades that lead to a pro-inflammatory cytokine response. Cancer, infection, and tissue damage can all modulate TLR9 expression and activation. TLR9 is also an important factor in autoimmune diseases, and there is active research into synthetic TLR9 agonists and antagonists that help regulate autoimmune inflammation. # Function The TLR family plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are named for the high degree of conservation in structure and function seen between mammalian TLRs and the Drosophila transmembrane protein Toll. TLRs are transmembrane proteins, expressed on the cell surface and the endocytic compartment and recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents and initiate signalling to induce production of cytokines necessary for the innate immunity and subsequent adaptive immunity. The various TLRs exhibit different patterns of expression. This gene is preferentially expressed in immune cell rich tissues, such as spleen, lymph node, bone marrow and peripheral blood leukocytes. Studies in mice and humans indicate that this receptor mediates cellular response to unmethylated CpG dinucleotides in bacterial DNA to mount an innate immune response. TLR9 is usually activated by unmethylated CpG sequences in DNA molecules. Once activated, TLR9 moves from the endoplasmic reticulum to the Golgi apparatus and lysosomes, where it interacts with MyD88, the primary protein in its signaling pathway. TLR9 is cleaved at this stage to avoid whole protein expression on cell surface, which could lead to autoimmunity. CpG sites are relatively rare (~1%) on vertebrate genomes in comparison to bacterial genomes or viral DNA. TLR9 is expressed by numerous cells of the immune system such as B lymphocytes, monocytes, natural killer (NK) cells, keratinocytes, melanocytes, and plasmacytoid dendritic cells. TLR9 is expressed intracellularly, within the endosomal compartments and functions to alert the immune system of viral and bacterial infections by binding to DNA rich in CpG motifs. TLR9 signals leads to activation of the cells initiating pro-inflammatory reactions that result in the production of cytokines such as type-I interferon, IL-6, TNF, IFNα, and IL-12. There is also recent evidence that TLR9 can recognize nucleotides other than unmethylated CpG present in bacterial or viral genomes. TLR9 has been shown to recognized DNA:RNA hybrids, but not ssDNA. # Role in non-viral cancer TLR9 expression progression during cancer varies greatly with the type of cancer. TLR9 may even present an exciting new marker for many cancer types. Breast cancer and renal cell carcinoma have both been shown to diminish expression of TLR9. In these cases higher levels correspond with better outcomes. Conversely studies have shown higher levels of TLR9 expression in breast cancer and ovarian cancer patients, and poor prognosis is associated with higher TLR9 expression in prostate cancer. Non-small cell lung cancer and glioma have also been shown to up-regulate the expression of TLR9. While these results are highly variable, it is clear that TLR9 expression increases the capacity for invasion and proliferation. Whether cancer induces modification of TLR9 expression or TLR9 expression hastens the onset of cancer is unclear, but many of the mechanisms that regulate cancer development also play a role in TLR9 expression. DNA damage and the p53 pathway influence TLR9 expression, and the hypoxic environment of tumor cells certainly induces expression of TLR9, further increases proliferation ability of the cancerous cells. Cellular stress has also been shown to relate to TLR9 expression. It is possible that cancer and TLR9 have a feed-forward relationship, where the occurrence of one leads to the up-regulation of the other. Many viruses take advantage of this relationship by inducing certain TLR9 expression patterns to first infect the cell (down-regulate) then trigger the onset of cancer (up-regulate). # Expression in oncogenic viral infection ## Human papilloma virus (HPV) Human papilloma virus is a deadly disease that, if left untreated, can lead to epithelial lesions and cervical cancer. HPV infection inhibits the expression of TLR9 in keratinocytes, abolishing the production of IL-8. However inhibition of TLR9 by oncogenic viruses is temporary, and patients with long-lasting HPV actually show higher levels of TLR9 expression in cervical cells. In fact, the increase in expression is so severe that TLR9 could be used as a biomarker for cervical cancer. The relationship between HPV-induced epithelial lesion, cancer progression, and TLR9 expression is still under investigation. ## Hepatitis B virus (HBV) Hepatitis B virus down-regulates the expression of TLR9 in pDCs and B cells, destroying the production of IFNα and IL-6. However, just as in HPV, as the disease progresses TLR9 expression is up-regulated. HBV induces an oncogenic transformation, which leads to a hypoxic cellular environment. This environment causes the release of mitochondrial DNA, which has CpG regions that can bind to TLR9. This induces over-expression of TLR9 in tumor cells, contrary to the inhibitory early stages of infection. ## Epstein-Barr virus (EBV) Epstein-Barr virus, like other oncogenic viruses, decreases the expression of TLR9 in B cells, diminishing production of TNF and IL-6. EBV has been reported to alter expression of TLR9 at the transcription, translation, and protein level. ## Polyomavirus The viruses of the polyomavirus family destroy expression of TLR9 in keratinocytes, inhibiting the release of IL-6 and IL-8. Expression is regulated at the promoter, where antigen proteins inhibit transcription. Similar to HPV and HBV infection, TLR9 expression increases as the disease progresses, probably due to the hypoxic nature of the solid tumor environment. # Clinical relevance of inflammation response TLR9 has been identified as a major player in systemic lupus erythematosus (SLE) and erythema nodosum leprosum (ENL). Loss of TLR9 exacerbates progression of SLE, and leads to increased activation of dentritic cells. TLR9 also controls the release of IgA and IFN-a in SLE, and loss of the receptor leads to higher levels of both molecules. In SLE, TLR9 and TLR7 have opposing effects. TLR9 regulates inflammatory response, while TLR7 promotes inflammatory response. TLR9 has an opposite effect in ENL. TLR9 is expressed at high levels on monocytes of ENL patients, and is positively linked to the secretion of proinflammatory cytokines TNF, IL-6, and IL-1β. TLR9 agonists and antagonists may be useful in treatment of a variety of inflammatory conditions, and research in this area is active. Autoimmune thyroid diseases have also been shown to correlate with an increase in expression of TLR9 on peripheral blood mononuclear cells (PBMCs). Patients with autoimmune thyroid diseases also have higher levels of the nuclear protein HMGB1 and RAGE protein, which together act as a ligand for TLR9. HMB1 is released from lysed or damaged cells. HMGB1-DNA complex then binds to RAGE, and activates TLR9. TLR9 can work through MyD88, an adaptor molecule that increases the expression of NF-kB. However autoimmune thyroid diseases also increase sensitivity of MyD88 independent pathways. These pathway ultimately leads to the production of pro-inflammatory cytokines in PMBCs for patients with autoimmune thyroid diseases. Autoimmune diseases can also be triggered by activated cells undergoing apoptosis and being engulfed by antigen presenting cells. Activation of cells leads to de-methylation, which exposes CpG regions of host DNA, allowing an inflammatory response to be activated through TLR9. Although it is possible that TLR9 also recognizes unmethylated DNA, TLR9 undoubtedly has a role in phagocytosis-induced autoimmunity. # Role in heart health Inflammatory responses mediated by TLR9 pathways can be activated by unmethylated CpG sequences that exist within human mitochondrial DNA. Usually, damaged mitochondria are digested via autophagy in cardiomyocytes, and mitochondrial DNA is digested by the enzyme DNase II. However mitochondria that escape digestion via the lysosome/autophagy pathway can activate TLR9-induced inflammation via the NF-kB pathway. TLR9 expression in hearts with pressure overload leads to increased inflammation due to damaged mitochondria and activation of the CpG binding cite on TLR9. There is evidence that TLR9 may play a role in heart heath for individuals who have already suffered a myocardial infarction. In murine trials, TLR9-deficient mice had less myofibroblast proliferation, meaning cardiac muscle recovery is connected to TLR9 expression. Furthermore, class B CpG sequences induce proliferation and differentiation of fibroblasts via the NF-kB pathway, the same pathway that initiates pro-inflammatory reactions in the immune responses. TLR9 shows specific activity in post-heart attack fibroblasts, inducing them to differentiate into myofibroblasts and speed repair of left ventricle tissue. In contrast to pre-myocardial infraction, cardiomyocytes in recovering hearts do not induce an inflammation response via TLR9/NF-kB pathway. Instead, the pathway leads to proliferation and differentiation of fibroblasts. # As an immunotherapy target There are new immunomodulatory treatments undergoing testing which involve the administration of artificial DNA oligonucleotides containing the CpG motif. CpG DNA has applications in treating allergies such as asthma, immunostimulation against cancer, immunostimulation against pathogens, and as adjuvants in vaccines. ## TLR9 agonists - Lefitolimod (MGN1703) has started clinical trials to treat (in combination with ipilimumab) patients with advanced solid malignancies. - Ongoing studies are investigating SD-101 (Dynavax) in combination with Keytruda (pembrolizumab), an anti-PD-1 therapy developed by Merck. - A Phase 1/2 trial is ongoing with tilsotolimod (IMO-2125, Idera, NASDAQ:IDRA) in combination with Yervoy (ipilimumab), an anti-CTLA-4 therapy developed by Bristol-Myers Squibb in anti-PD-1 refractory melanoma patients. FDA also granted fast track designation for tilsotolimod in combination with ipilimumab for treatment of PD-1 refractory metastatic melanoma. A phase 3 global trial in the same population is currently enrolling (Illuminate 301, NCT03445533). # Protein interactions - TLR9 has been shown to interact with RNF216. - Epidermal growth factor receptor (EGFR) is constitutively bound to TLR9. - It can be activated by CpG Oligodeoxynucleotides such as Agatolimod.

TLR9 Toll-like receptor 9 is a protein that in humans is encoded by the TLR9 gene.[1] TLR9 has also been designated as CD289 (cluster of differentiation 289). It is a member of the toll-like receptor (TLR) family. TLR9 is an important receptor expressed in immune system cells including dendritic cells, macrophages, natural killer cells, and other antigen presenting cells.[1] TLR9 preferentially binds DNA present in bacteria and viruses, and triggers signaling cascades that lead to a pro-inflammatory cytokine response.[2][3] Cancer, infection, and tissue damage can all modulate TLR9 expression and activation.[3][4][5][6][7] TLR9 is also an important factor in autoimmune diseases, and there is active research into synthetic TLR9 agonists and antagonists that help regulate autoimmune inflammation.[6][8] # Function The TLR family plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are named for the high degree of conservation in structure and function seen between mammalian TLRs and the Drosophila transmembrane protein Toll. TLRs are transmembrane proteins, expressed on the cell surface and the endocytic compartment and recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents and initiate signalling to induce production of cytokines necessary for the innate immunity and subsequent adaptive immunity. The various TLRs exhibit different patterns of expression.[4] This gene is preferentially expressed in immune cell rich tissues, such as spleen, lymph node, bone marrow and peripheral blood leukocytes. Studies in mice and humans indicate that this receptor mediates cellular response to unmethylated CpG dinucleotides in bacterial DNA to mount an innate immune response.[4] TLR9 is usually activated by unmethylated CpG sequences in DNA molecules. Once activated, TLR9 moves from the endoplasmic reticulum to the Golgi apparatus and lysosomes, where it interacts with MyD88, the primary protein in its signaling pathway.[2] TLR9 is cleaved at this stage to avoid whole protein expression on cell surface, which could lead to autoimmunity.[2] CpG sites are relatively rare (~1%) on vertebrate genomes in comparison to bacterial genomes or viral DNA. TLR9 is expressed by numerous cells of the immune system such as B lymphocytes, monocytes, natural killer (NK) cells, keratinocytes, melanocytes, and plasmacytoid dendritic cells. TLR9 is expressed intracellularly, within the endosomal compartments and functions to alert the immune system of viral and bacterial infections by binding to DNA rich in CpG motifs. TLR9 signals leads to activation of the cells initiating pro-inflammatory reactions that result in the production of cytokines such as type-I interferon, IL-6, TNF, IFNα, and IL-12.[2] There is also recent evidence that TLR9 can recognize nucleotides other than unmethylated CpG present in bacterial or viral genomes.[2] TLR9 has been shown to recognized DNA:RNA hybrids, but not ssDNA. # Role in non-viral cancer[2] TLR9 expression progression during cancer varies greatly with the type of cancer.[2] TLR9 may even present an exciting new marker for many cancer types. Breast cancer and renal cell carcinoma have both been shown to diminish expression of TLR9. In these cases higher levels correspond with better outcomes. Conversely studies have shown higher levels of TLR9 expression in breast cancer and ovarian cancer patients, and poor prognosis is associated with higher TLR9 expression in prostate cancer. Non-small cell lung cancer and glioma have also been shown to up-regulate the expression of TLR9. While these results are highly variable, it is clear that TLR9 expression increases the capacity for invasion and proliferation.[2] Whether cancer induces modification of TLR9 expression or TLR9 expression hastens the onset of cancer is unclear, but many of the mechanisms that regulate cancer development also play a role in TLR9 expression. DNA damage and the p53 pathway influence TLR9 expression, and the hypoxic environment of tumor cells certainly induces expression of TLR9, further increases proliferation ability of the cancerous cells. Cellular stress has also been shown to relate to TLR9 expression. It is possible that cancer and TLR9 have a feed-forward relationship, where the occurrence of one leads to the up-regulation of the other. Many viruses take advantage of this relationship by inducing certain TLR9 expression patterns to first infect the cell (down-regulate) then trigger the onset of cancer (up-regulate). # Expression in oncogenic viral infection[2] ## Human papilloma virus (HPV) Human papilloma virus is a deadly disease[clarification needed] that, if left untreated, can lead to epithelial lesions and cervical cancer.[2] HPV infection inhibits the expression of TLR9 in keratinocytes, abolishing the production of IL-8. However inhibition of TLR9 by oncogenic viruses is temporary, and patients with long-lasting HPV actually show higher levels of TLR9 expression in cervical cells. In fact, the increase in expression is so severe that TLR9 could be used as a biomarker for cervical cancer. The relationship between HPV-induced epithelial lesion, cancer progression, and TLR9 expression is still under investigation. ## Hepatitis B virus (HBV) Hepatitis B virus down-regulates the expression of TLR9 in pDCs and B cells, destroying the production of IFNα and IL-6.[2] However, just as in HPV, as the disease progresses TLR9 expression is up-regulated. HBV induces an oncogenic transformation, which leads to a hypoxic cellular environment. This environment causes the release of mitochondrial DNA, which has CpG regions that can bind to TLR9. This induces over-expression of TLR9 in tumor cells, contrary to the inhibitory early stages of infection. ## Epstein-Barr virus (EBV) Epstein-Barr virus, like other oncogenic viruses, decreases the expression of TLR9 in B cells, diminishing production of TNF and IL-6.[2] EBV has been reported to alter expression of TLR9 at the transcription, translation, and protein level. ## Polyomavirus The viruses of the polyomavirus family destroy expression of TLR9 in keratinocytes, inhibiting the release of IL-6 and IL-8.[2] Expression is regulated at the promoter, where antigen proteins inhibit transcription. Similar to HPV and HBV infection, TLR9 expression increases as the disease progresses, probably due to the hypoxic nature of the solid tumor environment. # Clinical relevance of inflammation response TLR9 has been identified as a major player in systemic lupus erythematosus (SLE) and erythema nodosum leprosum (ENL).[5][6] Loss of TLR9 exacerbates progression of SLE, and leads to increased activation of dentritic cells.[6] TLR9 also controls the release of IgA and IFN-a in SLE, and loss of the receptor leads to higher levels of both molecules. In SLE, TLR9 and TLR7 have opposing effects. TLR9 regulates inflammatory response, while TLR7 promotes inflammatory response. TLR9 has an opposite effect in ENL.[5] TLR9 is expressed at high levels on monocytes of ENL patients, and is positively linked to the secretion of proinflammatory cytokines TNF, IL-6, and IL-1β. TLR9 agonists and antagonists may be useful in treatment of a variety of inflammatory conditions, and research in this area is active. Autoimmune thyroid diseases have also been shown to correlate with an increase in expression of TLR9 on peripheral blood mononuclear cells (PBMCs).[8] Patients with autoimmune thyroid diseases also have higher levels of the nuclear protein HMGB1 and RAGE protein, which together act as a ligand for TLR9. HMB1 is released from lysed or damaged cells. HMGB1-DNA complex then binds to RAGE, and activates TLR9. TLR9 can work through MyD88, an adaptor molecule that increases the expression of NF-kB. However autoimmune thyroid diseases also increase sensitivity of MyD88 independent pathways.[8] These pathway ultimately leads to the production of pro-inflammatory cytokines in PMBCs for patients with autoimmune thyroid diseases. Autoimmune diseases can also be triggered by activated cells undergoing apoptosis and being engulfed by antigen presenting cells.[3] Activation of cells leads to de-methylation, which exposes CpG regions of host DNA, allowing an inflammatory response to be activated through TLR9.[3] Although it is possible that TLR9 also recognizes unmethylated DNA, TLR9 undoubtedly has a role in phagocytosis-induced autoimmunity. # Role in heart health Inflammatory responses mediated by TLR9 pathways can be activated by unmethylated CpG sequences that exist within human mitochondrial DNA.[9][10] Usually, damaged mitochondria are digested via autophagy in cardiomyocytes, and mitochondrial DNA is digested by the enzyme DNase II. However mitochondria that escape digestion via the lysosome/autophagy pathway can activate TLR9-induced inflammation via the NF-kB pathway. TLR9 expression in hearts with pressure overload leads to increased inflammation due to damaged mitochondria and activation of the CpG binding cite on TLR9. There is evidence that TLR9 may play a role in heart heath for individuals who have already suffered a myocardial infarction.[7] In murine trials, TLR9-deficient mice had less myofibroblast proliferation, meaning cardiac muscle recovery is connected to TLR9 expression. Furthermore, class B CpG sequences induce proliferation and differentiation of fibroblasts via the NF-kB pathway, the same pathway that initiates pro-inflammatory reactions in the immune responses. TLR9 shows specific activity in post-heart attack fibroblasts, inducing them to differentiate into myofibroblasts and speed repair of left ventricle tissue. In contrast to pre-myocardial infraction, cardiomyocytes in recovering hearts do not induce an inflammation response via TLR9/NF-kB pathway. Instead, the pathway leads to proliferation and differentiation of fibroblasts. # As an immunotherapy target There are new immunomodulatory treatments undergoing testing which involve the administration of artificial DNA oligonucleotides containing the CpG motif. CpG DNA has applications in treating allergies such as asthma,[11] immunostimulation against cancer,[12] immunostimulation against pathogens, and as adjuvants in vaccines.[13] ## TLR9 agonists - Lefitolimod (MGN1703) has started clinical trials to treat (in combination with ipilimumab) patients with advanced solid malignancies.[14] - Ongoing studies are investigating SD-101 (Dynavax) in combination with Keytruda (pembrolizumab), an anti-PD-1 therapy developed by Merck. [15] - A Phase 1/2 trial is ongoing with tilsotolimod (IMO-2125, Idera, NASDAQ:IDRA) in combination with Yervoy (ipilimumab), an anti-CTLA-4 therapy developed by Bristol-Myers Squibb in anti-PD-1 refractory melanoma patients.[16] FDA also granted fast track designation for tilsotolimod in combination with ipilimumab for treatment of PD-1 refractory metastatic melanoma.[17] A phase 3 global trial in the same population is currently enrolling (Illuminate 301, NCT03445533). # Protein interactions - TLR9 has been shown to interact with RNF216.[18] - Epidermal growth factor receptor (EGFR) is constitutively bound to TLR9.[19] - It can be activated by CpG Oligodeoxynucleotides such as Agatolimod.

https://www.wikidoc.org/index.php/TLR9

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wikidoc

TMC1

TMC1 Transmembrane channel-like protein 1 is a protein that in humans is encoded by the TMC1 gene. TMC1 contains six transmembrane domains with both the C and N termini on the endoplasmic side of the membrane, as well as a large loop between domains 4 and 5. This topology is similar to that of transient receptor potential channels (TRPs), a family of proteins involved in the perception of senses such as temperature, taste, pressure, and vision. TMC1 has been located in the post-natal mouse cochlea, and knockouts for TMC1 and TMC2 result in both auditory and vestibular deficits (hearing loss and balance issues) indicating TMC1 is a molecular part of auditory transduction. # Function This gene is considered a member of a gene family predicted to encode transmembrane proteins. Until recently, the specific function of this gene was relatively unknown; it was only known to be required for normal function of cochlear hair cells. However, new research suggests that TMC1 interacts with Tip link proteins protocadherin 15 and cadherin 23 indicating that TMC1, along with TMC2, are necessary proteins for hair cell mechanotransduction. Specifically, TMC1 and TMC2 may be two pore-forming subunits of the channel that responds to tip link deflection in hair cells. Due to its implication in cochlear hair cell function and its interaction with hair cell tip links, TMC1 is being mutated and manipulated in order to better understand the receptor while at the same time producing a molecular model for deafness. While deafness can arise at any stage of auditory processing, DFNA36 (a type of progressive hearing loss) and DFNB7/B11 (congenital hearing loss) have been specifically shown to arise from TMC1 mutations. DFNA36 results from a dominant missense mutation and DFNB7/B11 results from a recessive mutation. Both have been modeled in mice, known as the Beethoven model and the dn model respectively. The TMC1 gene is located on chromosome 9q31-q21, and the dominant mutation associated with DFNA36 occurs at amino acid 572 which suggests the importance of this amino acid in the overall function of TMC1. Now that TMC1 has been shown to interact with the tip link proteins PCDH15 and CDH23, the next question may be whether or not amino acid 572 is necessary for TMC1 tip link interactions. Researchers reported in 2015 that genetically deaf mice treated with TMC1 gene therapy recovered some of their hearing. # Clinical significance Mutations in this gene have been associated with progressive postlingual hearing loss, non syndromic deafness and profound prelingual deafness. TMC1 mutations are not associated with other symptoms or abnormalities, which is known as Nonsyndromic hearing loss and indicates that TMC1 functions mainly in auditory sensation. Additionally, recessive mutations of the gene result in both a loss of TMC1 function as well as profound deafness indicating TMC1 function is necessary for the processing of auditory signals.

TMC1 Transmembrane channel-like protein 1 is a protein that in humans is encoded by the TMC1 gene.[1][2][3] TMC1 contains six transmembrane domains with both the C and N termini on the endoplasmic side of the membrane, as well as a large loop between domains 4 and 5. This topology is similar to that of transient receptor potential channels (TRPs),[1] a family of proteins involved in the perception of senses such as temperature, taste, pressure, and vision.[4] TMC1 has been located in the post-natal mouse cochlea,[1] and knockouts for TMC1 and TMC2 result in both auditory and vestibular deficits (hearing loss and balance issues) indicating TMC1 is a molecular part of auditory transduction.[5] # Function This gene is considered a member of a gene family predicted to encode transmembrane proteins. Until recently, the specific function of this gene was relatively unknown; it was only known to be required for normal function of cochlear hair cells.[3] However, new research suggests that TMC1 interacts with Tip link proteins protocadherin 15 and cadherin 23 indicating that TMC1, along with TMC2, are necessary proteins for hair cell mechanotransduction.[6] Specifically, TMC1 and TMC2 may be two pore-forming subunits of the channel that responds to tip link deflection in hair cells.[7] Due to its implication in cochlear hair cell function and its interaction with hair cell tip links, TMC1 is being mutated and manipulated in order to better understand the receptor while at the same time producing a molecular model for deafness. While deafness can arise at any stage of auditory processing, DFNA36 (a type of progressive hearing loss) and DFNB7/B11 (congenital hearing loss) have been specifically shown to arise from TMC1 mutations. DFNA36 results from a dominant missense mutation and DFNB7/B11 results from a recessive mutation.[1] Both have been modeled in mice, known as the Beethoven model and the dn model respectively.[2] The TMC1 gene is located on chromosome 9q31-q21, and the dominant mutation associated with DFNA36 occurs at amino acid 572[8] which suggests the importance of this amino acid in the overall function of TMC1. Now that TMC1 has been shown to interact with the tip link proteins PCDH15 and CDH23,[6] the next question may be whether or not amino acid 572 is necessary for TMC1 tip link interactions. Researchers reported in 2015 that genetically deaf mice treated with TMC1 gene therapy recovered some of their hearing.[9][10] # Clinical significance Mutations in this gene have been associated with progressive postlingual hearing loss, non syndromic deafness [11] and profound prelingual deafness.[3] TMC1 mutations are not associated with other symptoms or abnormalities, which is known as Nonsyndromic hearing loss and indicates that TMC1 functions mainly in auditory sensation.[12] Additionally, recessive mutations of the gene result in both a loss of TMC1 function as well as profound deafness[8] indicating TMC1 function is necessary for the processing of auditory signals.

https://www.wikidoc.org/index.php/TMC1

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wikidoc

TMC2

TMC2 Transmembrane channel-like protein 2 is a protein that in humans is encoded by the TMC2 gene. # Function This gene is considered a member of a gene family predicted to encode transmembrane proteins. The specific function of this gene is unknown; however, expression in the inner ear suggests that it may be crucial for normal auditory function. # Clinical significance Mutations in this gene may underlie hereditary disorders of balance and hearing.

TMC2 Transmembrane channel-like protein 2 is a protein that in humans is encoded by the TMC2 gene.[1][2][3] # Function This gene is considered a member of a gene family predicted to encode transmembrane proteins. The specific function of this gene is unknown; however, expression in the inner ear suggests that it may be crucial for normal auditory function.[3] # Clinical significance Mutations in this gene may underlie hereditary disorders of balance and hearing.[3]

https://www.wikidoc.org/index.php/TMC2

206f814685e12da823424649ba70890e7896e82e

wikidoc

TMC8

TMC8 Transmembrane channel-like 8 is a protein which in humans is encoded by the TMC8 gene. # Function The protein encoded by this gene is an integral membrane protein that localize to the endoplasmic reticulum and is predicted to form transmembrane channels. This gene encodes a transmembrane channel-like protein with 8 predicted transmembrane domains and 3 leucine zipper motifs. # Clinical significance Mutations in the TMC8 gene are associated with epidermodysplasia verruciformis (EV), an autosomal recessive dermatosis characterized by abnormal susceptibility to human papillomaviruses (HPVs) and a high rate of progression to squamous cell carcinoma on sun-exposed skin.

TMC8 Transmembrane channel-like 8 is a protein which in humans is encoded by the TMC8 gene.[1][2] # Function The protein encoded by this gene is an integral membrane protein that localize to the endoplasmic reticulum and is predicted to form transmembrane channels. This gene encodes a transmembrane channel-like protein with 8 predicted transmembrane domains and 3 leucine zipper motifs.[2] # Clinical significance Mutations in the TMC8 gene are associated with epidermodysplasia verruciformis (EV), an autosomal recessive dermatosis characterized by abnormal susceptibility to human papillomaviruses (HPVs) and a high rate of progression to squamous cell carcinoma on sun-exposed skin.[2]

https://www.wikidoc.org/index.php/TMC8

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wikidoc

TNIK

TNIK TRAF2 and NCK-interacting protein kinase is an enzyme that in humans is encoded by the TNIK gene. # Function Germinal center kinases (GCKs), such as TNIK, are characterized by an N-terminal kinase domain and a C-terminal GCK domain that serves a regulatory function. # Interactions TNIK has been shown to interact with KIAA0090, although the significance is unclear. TNIK has been shown to phosphorylate Gelsolin, a protein involved in F-actin depolymerisation thus inducing cytoskeletal changes.

TNIK TRAF2 and NCK-interacting protein kinase is an enzyme that in humans is encoded by the TNIK gene.[1][2][3] # Function Germinal center kinases (GCKs), such as TNIK, are characterized by an N-terminal kinase domain and a C-terminal GCK domain that serves a regulatory function.[2][3] # Interactions TNIK has been shown to interact with KIAA0090,[4] although the significance is unclear. TNIK has been shown to phosphorylate Gelsolin, a protein involved in F-actin depolymerisation thus inducing cytoskeletal changes.[2]

https://www.wikidoc.org/index.php/TNIK

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wikidoc

TNK2

TNK2 Activated CDC42 kinase 1, also known as ACK1, is an enzyme that in humans is encoded by the TNK2 gene. TNK2 gene encodes a non-receptor tyrosine kinase, ACK1, that binds to multiple receptor tyrosine kinases e.g. EGFR, MERTK, AXL, HER2 and insulin receptor (IR). ACK1 also interacts with Cdc42Hs in its GTP-bound form and inhibits both the intrinsic and GTPase-activating protein (GAP)-stimulated GTPase activity of Cdc42Hs. This binding is mediated by a unique sequence of 47 amino acids C-terminal to an SH3 domain. The protein may be involved in a regulatory mechanism that sustains the GTP-bound active form of Cdc42Hs and which is directly linked to a tyrosine phosphorylation signal transduction pathway. Several alternatively spliced transcript variants have been identified from this gene, but the full-length nature of only two transcript variants has been determined. # Interactions ACK1 or TNK2 has been shown to interact with AKT, Androgen receptor or AR, a tumor suppressor WWOX, FYN and Grb2. ACK1 interaction with its substrates resulted in their phosphorylation at specific tyrosine residues. ACK1 has been shown to directly phosphorylate AKT at tyrosine 176, AR at Tyrosine 267 and 363, and WWOX at tyrosine 287 residues, respectively. ACK1-AR signaling has also been reported to regulate ATM levels, # Clinical relevance ACK1 is a survival kinase and shown to be associated with tumor cell survival, proliferation, hormone-resistance and radiation resistance. The activation of ACK1 has been observed in prostate, breast, pancreatic, lung and ovarian cancer cells. ACK1 transgenic mice, expressing activated ACK1 specifically in prostate gland has been reported; these mice develop prostatic intraepithelial neoplasia (PINs). # ACK1 inhibitors Ack1 has emerged as a new cancer target and multiple small molecule inhibitors have been reported. All of these inhibitors are currently in the pre-clinical stage.

TNK2 Activated CDC42 kinase 1, also known as ACK1, is an enzyme that in humans is encoded by the TNK2 gene. [1][2][3][4][5] TNK2 gene encodes a non-receptor tyrosine kinase, ACK1, that binds to multiple receptor tyrosine kinases e.g. EGFR, MERTK, AXL, HER2 and insulin receptor (IR). ACK1 also interacts with Cdc42Hs in its GTP-bound form and inhibits both the intrinsic and GTPase-activating protein (GAP)-stimulated GTPase activity of Cdc42Hs. This binding is mediated by a unique sequence of 47 amino acids C-terminal to an SH3 domain. The protein may be involved in a regulatory mechanism that sustains the GTP-bound active form of Cdc42Hs and which is directly linked to a tyrosine phosphorylation signal transduction pathway. Several alternatively spliced transcript variants have been identified from this gene, but the full-length nature of only two transcript variants has been determined.[5] # Interactions ACK1 or TNK2 has been shown to interact with AKT,[3] Androgen receptor or AR,[6] a tumor suppressor WWOX,[7] FYN[8] and Grb2.[9][10] ACK1 interaction with its substrates resulted in their phosphorylation at specific tyrosine residues. ACK1 has been shown to directly phosphorylate AKT at tyrosine 176, AR at Tyrosine 267 and 363, and WWOX at tyrosine 287 residues, respectively. ACK1-AR signaling has also been reported to regulate ATM levels,[11] # Clinical relevance ACK1 is a survival kinase and shown to be associated with tumor cell survival, proliferation, hormone-resistance and radiation resistance.[1] The activation of ACK1 has been observed in prostate, breast, pancreatic, lung and ovarian cancer cells.[1][3][6][12] ACK1 transgenic mice, expressing activated ACK1 specifically in prostate gland has been reported; these mice develop prostatic intraepithelial neoplasia (PINs).[3] # ACK1 inhibitors Ack1 has emerged as a new cancer target and multiple small molecule inhibitors have been reported.[13] [14][15] All of these inhibitors are currently in the pre-clinical stage.

https://www.wikidoc.org/index.php/TNK2

c0f97328f026f55beb13e13d0128c9fe954fd5ae

wikidoc

TOP1

TOP1 DNA topoisomerase 1 is an enzyme that in humans is encoded by the TOP1 gene. # Function This gene encodes a DNA topoisomerase, an enzyme that controls and alters the topologic states of DNA during transcription. This enzyme catalyzes the transient breaking and rejoining of a single strand of DNA which lets the broken strand rotate around the intact strand, thus altering the topology of DNA. This gene is localized to chromosome 20 and has pseudogenes which reside on chromosomes 1 and 22. # Mechanism As reviewed by Champoux, the type IB topoisomerases, including TOP1, form a covalent intermediate in which the active site tyrosine becomes attached to the 3' phosphate end of the cleaved strand rather than the 5' phosphate end. The eukaryotic topoisomerases I were found to nick the DNA with a preference for a sequence of nucleotides that extends from positions -4 to -1 from the nick. The preferred nucleotides in the strand to be cut are 5'-(A/T)(G/C)(A/T)T-3' with the enzyme covalently attached to the -1 T residue, though sometimes a C residue is found at the -1 position. The TOP1 protein of humans has been subdivided into four regions. The N-terminal 214 amino acids are dispensable for relaxation of supercoiling activity in vitro and there are four nuclear localization signals and sites for interaction with other cellular proteins within the N-terminal domain. The N-terminal domain is followed by a highly conserved, 421 amino acid core domain containing all of the catalytic residues except the active site tyrosine. This is followed by a poorly conserved linker domain of 77 amino acids. Finally there is a 53 amino acid C-terminal domain. The active site Tyr723 is found within the C-terminal domain. As further summarized by Pommier and by Seol et al., TOP1 breaks the DNA by a transesterification reaction using the active site tyrosine as the nucleophile that attacks the DNA phosphodiester backbone. After the TOP1 covalently attaches to the 3' end of the broken strand, supercoiling of the DNA is relaxed by controlled rotation of DNA about the intact strand. Then the 5' hydroxyl end of the broken DNA strand can reverse the phosphotyrosyl bond, enabling the release of TOP1 and religation of the DNA. The nicking and closing reactions are fast, and about 100 cycles can occur per second. # Inhibition The briefly attached, covalently bonded TOP1-DNA structure at the 3' end of a cleaved DNA single strand is called a TOP1-DNA cleavage complex, or TOP1cc. The TOP1cc is a specific target of TOP1 inhibitors. One of the first inhibitors shown to target TOP1 is irinotecan. Irinotecan is an analogue of the cytotoxic natural alkaloid camptothecin, obtained from the Chinese tree Camptotheca acuminata. Irinotecan is especially effective through its metabolic product SN-38. Irinotecan and SN-38 act by trapping a subset of TOP1-DNA cleavage complexes, those with a guanine +1 in the DNA sequence. One irinotecan or SN-38 molecule stacks against the base pairs flanking the topoisomerase-induced cleavage site and poisons (inactivates) the TOP1 enzyme. The article Camptothecin lists other analogues of camptothecin and the article Topoisomerase inhibitor lists other compounds which inhibit TOP1. # Cancer Since 1985, TOP1 has been known as a target for the treatment of human cancers. Camptothecin analogues irinotecan and topotecan, which inhibit TOP1, are among the most effective FDA-approved anticancer chemotherapeutic agents used in clinical practice. Higher expression of TOP1 in KRAS mutant non-small cell lung cancer and correlation to survival suggests that TOP1 inhibitors might have increased benefit when administered to treat patients with a KRAS mutant tumor. ## Synthetic lethality Synthetic lethality arises when a combination of deficiencies in the expression of two or more genes leads to cell death, whereas a deficiency in only one of these genes does not. The deficiencies can arise through mutation, epigenetic alteration or by inhibition of a gene's expression. Irinotecan inactivation of TOP1 appears to be synthetically lethal in combination with deficiencies in expression of some specific DNA repair genes. Irinotecan inactivation of TOP1 was synthetically lethal with deficient expression of the DNA repair WRN gene in patients with colon cancer. In a 2006 study, 45 patients had colonic tumors with hypermethylated WRN gene promoters (silenced WRN expression), and 43 patients had tumors with unmethylated WRN gene promoters, so that WRN protein expression was high. Irinotecan was more strongly beneficial for patients with hypermethylated WRN promoters (39.4 months survival) than for those with unmethylated WRN promoters (20.7 months survival). The WRN gene promoter is hypermethylated in about 38% of colorectal cancers. Irinotecan inactivation of TOP1 may be synthetically lethal with deficient expression of DNA repair gene MRE11. A recent study was carried out with 1,264 patients with stage III colon cancer. The patients were treated with a postoperative weekly adjuvant bolus of 5-fluorouracil/leucovorin (FU/LV) or else with irinotecan+FU/LV and were followed up for 8 years. Eleven percent of the tumors were deficient for DNA repair enzyme MRE11 due to a deletion of a string of thymidines in the DNA sequence of the MRE11 gene. The addition of irinotecan to FU/LV in the treatment protocol resulted in MRE11-deficient patients having better long-term disease free survival than patients with wild-type MRE11 (though the effect was small), indicating some degree of synthetic lethality between irinotecan-induced TOP1 inactivation and MRE11 deficiency. There are a number of pre-clinical studies indicating synthetic lethality of irinotecan with other genetic or epigenetic DNA repair deficiencies common in cancers. For instance, the DNA repair gene ATM is frequently hypermethylated (silenced) in many cancers (see hypermethylation of ATM in cancers). A 2016 study showed that low expression of the ATM protein in gastric cancer cells in vitro and in a mouse model caused increased sensitivity to inactivation by irinotecan compared to cells with high expression of ATM. This indicates synthetic lethality of ATM deficiency with irinotecan-mediated TOP1 deficiency. Another pre-clinical effort was a screening study to find a compound that would be synthetically lethal with a deficiency of N-myc downstream regulated gene 1 (NDRG1) expression. NDRG1 is a metastasis-suppressor gene in prostate cancer, and appears to have a role in DNA repair. Screening of 3360 compounds revealed that irinotecan-mediated TOP1 deficiency (and one other compound, cetrimonium bromide) exhibit synthetic lethality with NDRG1 deficiency in prostate cancer cells. # Interactions TOP1 has been shown to interact with: - ASF/SF2, - BTBD1, - BTBD2, - Nucleolin, - P53, and - UBE2I.

TOP1 DNA topoisomerase 1 is an enzyme that in humans is encoded by the TOP1 gene. # Function This gene encodes a DNA topoisomerase, an enzyme that controls and alters the topologic states of DNA during transcription. This enzyme catalyzes the transient breaking and rejoining of a single strand of DNA which lets the broken strand rotate around the intact strand,[1] thus altering the topology of DNA. This gene is localized to chromosome 20 and has pseudogenes which reside on chromosomes 1 and 22.[2] # Mechanism As reviewed by Champoux,[3] the type IB topoisomerases, including TOP1, form a covalent intermediate in which the active site tyrosine becomes attached to the 3' phosphate end of the cleaved strand rather than the 5' phosphate end. The eukaryotic topoisomerases I were found to nick the DNA with a preference for a sequence of nucleotides that extends from positions -4 to -1 from the nick. The preferred nucleotides in the strand to be cut are 5'-(A/T)(G/C)(A/T)T-3' with the enzyme covalently attached to the -1 T residue, though sometimes a C residue is found at the -1 position. The TOP1 protein of humans has been subdivided into four regions. The N-terminal 214 amino acids are dispensable for relaxation of supercoiling activity in vitro and there are four nuclear localization signals and sites for interaction with other cellular proteins within the N-terminal domain. The N-terminal domain is followed by a highly conserved, 421 amino acid core domain containing all of the catalytic residues except the active site tyrosine. This is followed by a poorly conserved linker domain of 77 amino acids. Finally there is a 53 amino acid C-terminal domain. The active site Tyr723 is found within the C-terminal domain. As further summarized by Pommier and by Seol et al.,[1][4] TOP1 breaks the DNA by a transesterification reaction using the active site tyrosine as the nucleophile that attacks the DNA phosphodiester backbone. After the TOP1 covalently attaches to the 3' end of the broken strand, supercoiling of the DNA is relaxed by controlled rotation of DNA about the intact strand. Then the 5' hydroxyl end of the broken DNA strand can reverse the phosphotyrosyl bond, enabling the release of TOP1 and religation of the DNA. The nicking and closing reactions are fast, and about 100 cycles can occur per second. # Inhibition The briefly attached, covalently bonded TOP1-DNA structure at the 3' end of a cleaved DNA single strand is called a TOP1-DNA cleavage complex, or TOP1cc. The TOP1cc is a specific target of TOP1 inhibitors. One of the first inhibitors shown to target TOP1 is irinotecan. Irinotecan is an analogue of the cytotoxic natural alkaloid camptothecin, obtained from the Chinese tree Camptotheca acuminata.[5] Irinotecan is especially effective through its metabolic product SN-38. Irinotecan and SN-38 act by trapping a subset of TOP1-DNA cleavage complexes, those with a guanine +1 in the DNA sequence.[1] One irinotecan or SN-38 molecule stacks against the base pairs flanking the topoisomerase-induced cleavage site and poisons (inactivates) the TOP1 enzyme.[1] The article Camptothecin lists other analogues of camptothecin and the article Topoisomerase inhibitor lists other compounds which inhibit TOP1. # Cancer Since 1985, TOP1 has been known as a target for the treatment of human cancers.[5] Camptothecin analogues irinotecan and topotecan, which inhibit TOP1, are among the most effective FDA-approved anticancer chemotherapeutic agents used in clinical practice. Higher expression of TOP1 in KRAS mutant non-small cell lung cancer and correlation to survival suggests that TOP1 inhibitors might have increased benefit when administered to treat patients with a KRAS mutant tumor.[6] ## Synthetic lethality Synthetic lethality arises when a combination of deficiencies in the expression of two or more genes leads to cell death, whereas a deficiency in only one of these genes does not. The deficiencies can arise through mutation, epigenetic alteration or by inhibition of a gene's expression. Irinotecan inactivation of TOP1 appears to be synthetically lethal in combination with deficiencies in expression of some specific DNA repair genes. Irinotecan inactivation of TOP1 was synthetically lethal with deficient expression of the DNA repair WRN gene in patients with colon cancer.[7] In a 2006 study, 45 patients had colonic tumors with hypermethylated WRN gene promoters (silenced WRN expression), and 43 patients had tumors with unmethylated WRN gene promoters, so that WRN protein expression was high.[7] Irinotecan was more strongly beneficial for patients with hypermethylated WRN promoters (39.4 months survival) than for those with unmethylated WRN promoters (20.7 months survival). The WRN gene promoter is hypermethylated in about 38% of colorectal cancers.[7] Irinotecan inactivation of TOP1 may be synthetically lethal with deficient expression of DNA repair gene MRE11. A recent study was carried out with 1,264 patients with stage III colon cancer.[8] The patients were treated with a postoperative weekly adjuvant bolus of 5-fluorouracil/leucovorin (FU/LV) or else with irinotecan+FU/LV and were followed up for 8 years. Eleven percent of the tumors were deficient for DNA repair enzyme MRE11 due to a deletion of a string of thymidines in the DNA sequence of the MRE11 gene. The addition of irinotecan to FU/LV in the treatment protocol resulted in MRE11-deficient patients having better long-term disease free survival than patients with wild-type MRE11 (though the effect was small), indicating some degree of synthetic lethality between irinotecan-induced TOP1 inactivation and MRE11 deficiency.[8] There are a number of pre-clinical studies indicating synthetic lethality of irinotecan with other genetic or epigenetic DNA repair deficiencies common in cancers. For instance, the DNA repair gene ATM is frequently hypermethylated (silenced) in many cancers (see hypermethylation of ATM in cancers). A 2016 study showed that low expression of the ATM protein in gastric cancer cells in vitro and in a mouse model caused increased sensitivity to inactivation by irinotecan compared to cells with high expression of ATM.[9] This indicates synthetic lethality of ATM deficiency with irinotecan-mediated TOP1 deficiency.[9] Another pre-clinical effort was a screening study to find a compound that would be synthetically lethal with a deficiency of N-myc downstream regulated gene 1 (NDRG1) expression. NDRG1 is a metastasis-suppressor gene in prostate cancer,[10] and appears to have a role in DNA repair.[11] Screening of 3360 compounds revealed that irinotecan-mediated TOP1 deficiency (and one other compound, cetrimonium bromide) exhibit synthetic lethality with NDRG1 deficiency in prostate cancer cells.[10] # Interactions TOP1 has been shown to interact with: - ASF/SF2,[12][13] - BTBD1,[14] - BTBD2,[14] - Nucleolin,[15][16] - P53,[17][18] and - UBE2I.[19]

https://www.wikidoc.org/index.php/TOP1

1dda46da908a2567c1c25870088b504807742526

wikidoc

TOX3

TOX3 TOX high mobility group box family member 3, also known as TOX3, is a human gene. The protein encoded by this gene is a member of a subfamily of transcription factors that also includes TOX, TOX2, and TOX4 that share almost identical HMG-box DNA-binding domains which function to modify chromatin structure. # Disease linkage Mutations in the TOX3 gene are associated with an increased risk of breast cancer.

TOX3 TOX high mobility group box family member 3, also known as TOX3, is a human gene.[1][2] The protein encoded by this gene is a member of a subfamily of transcription factors that also includes TOX, TOX2, and TOX4 that share almost identical HMG-box DNA-binding domains which function to modify chromatin structure.[2] # Disease linkage Mutations in the TOX3 gene are associated with an increased risk of breast cancer.[3][4][5][6]

https://www.wikidoc.org/index.php/TOX3

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wikidoc

TP53

TP53 Tumor protein p53, also known as p53, cellular tumor antigen p53 (UniProt name), phosphoprotein p53, tumor suppressor p53, antigen NY-CO-13, or transformation-related protein 53 (TRP53), is any isoform of a protein encoded by homologous genes in various organisms, such as TP53 (humans) and Trp53 (mice). This homolog (originally thought to be, and often spoken of as, a single protein) is crucial in multicellular organisms, where it prevents cancer formation, thus, functions as a tumor suppressor. As such, p53 has been described as "the guardian of the genome" because of its role in conserving stability by preventing genome mutation. Hence TP53 is classified as a tumor suppressor gene. (Italics are used to denote the TP53 gene name and distinguish it from the protein it encodes.) The name p53 was given in 1979 describing the apparent molecular mass; SDS-PAGE analysis indicates that it is a 53-kilodalton (kDa) protein. However, the actual mass of the full-length p53 protein (p53α) based on the sum of masses of the amino acid residues is only 43.7 kDa. This difference is due to the high number of proline residues in the protein, which slow its migration on SDS-PAGE, thus making it appear heavier than it actually is. In addition to the full-length protein, the human TP53 gene encodes at least 15 protein isoforms, ranging in size from 3.5 to 43.7 kDa. All these p53 proteins are called the p53 isoforms. The TP53 gene is the most frequently mutated gene (>50%) in human cancer, indicating that the TP53 gene plays a crucial role in preventing cancer formation. TP53 gene encodes proteins that bind to DNA and regulate gene expression to prevent mutations of the genome. # Gene In humans, the TP53 gene is located on the short arm of chromosome 17 (17p13.1). The gene spans 20 kb, with a non-coding exon 1 and a very long first intron of 10 kb. The coding sequence contains five regions showing a high degree of conservation in vertebrates, predominantly in exons 2, 5, 6, 7 and 8, but the sequences found in invertebrates show only distant resemblance to mammalian TP53. TP53 orthologs have been identified in most mammals for which complete genome data are available. In humans, a common polymorphism involves the substitution of an arginine for a proline at codon position 72. Many studies have investigated a genetic link between this variation and cancer susceptibility; however, the results have been controversial. For instance, a meta-analysis from 2009 failed to show a link for cervical cancer. A 2011 study found that the TP53 proline mutation did have a profound effect on pancreatic cancer risk among males. A study of Arab women found that proline homozygosity at TP53 codon 72 is associated with a decreased risk for breast cancer. One study suggested that TP53 codon 72 polymorphisms, MDM2 SNP309, and A2164G may collectively be associated with non-oropharyngeal cancer susceptibility and that MDM2 SNP309 in combination with TP53 codon 72 may accelerate the development of non-oropharyngeal cancer in women. A 2011 study found that TP53 codon 72 polymorphism was associated with an increased risk of lung cancer. Meta-analyses from 2011 found no significant associations between TP53 codon 72 polymorphisms and both colorectal cancer risk and endometrial cancer risk. A 2011 study of a Brazilian birth cohort found an association between the non mutant arginine TP53 and individuals without a family history of cancer. Another 2011 study found that the p53 homozygous (Pro/Pro) genotype was associated with a significantly increased risk for renal cell carcinoma. # Structure - an acidic N-terminus transcription-activation domain (TAD), also known as activation domain 1 (AD1), which activates transcription factors. The N-terminus contains two complementary transcriptional activation domains, with a major one at residues 1–42 and a minor one at residues 55–75, specifically involved in the regulation of several pro-apoptotic genes. - activation domain 2 (AD2) important for apoptotic activity: residues 43-63. - proline rich domain important for the apoptotic activity of p53 by nuclear exportation via MAPK: residues 64-92. - central DNA-binding core domain (DBD). Contains one zinc atom and several arginine amino acids: residues 102-292. This region is responsible for binding the p53 co-repressor LMO3. - nuclear localization signaling domain, residues 316-325. - homo-oligomerisation domain (OD): residues 307-355. Tetramerization is essential for the activity of p53 in vivo. - C-terminal involved in downregulation of DNA binding of the central domain: residues 356-393. A tandem of nine-amino-acid transactivation domains (9aaTAD) was identified in the AD1 and AD2 regions of transcription factor p53. KO mutations and position for p53 interaction with TFIID are listed below: The competence of the p53 transactivation domains 9aaTAD to activate transcription as small peptides was reported. File:Piskacek p53b.jpg p53 transactivation Piskacek M, Havelka M, Rezacova M, Knight A. "The 9aaTAD Transactivation Domains: From Gal4 to p53". PLoS ONE. 11: e0162842. doi:10.1371/journal.pone.0162842. PMC 5019370. PMID 27618436. 9aaTADs mediate p53 interaction with general coactivators – TAF9, CBP/p300 (all four domains KIX, TAZ1, TAZ2 and IBiD), GCN5 and PC4, regulatory protein MDM2 and replication protein A (RPA). File:Piskacek p53a.jpg p53 conversion Piskacek M, Havelka M, Rezacova M, Knight A. "The 9aaTAD Transactivation Domains: From Gal4 to p53". PLoS ONE. 11: e0162842. doi:10.1371/journal.pone.0162842. PMC 5019370. PMID 27618436. Mutations that deactivate p53 in cancer usually occur in the DBD. Most of these mutations destroy the ability of the protein to bind to its target DNA sequences, and thus prevents transcriptional activation of these genes. As such, mutations in the DBD are recessive loss-of-function mutations. Molecules of p53 with mutations in the OD dimerise with wild-type p53, and prevent them from activating transcription. Therefore, OD mutations have a dominant negative effect on the function of p53. Wild-type p53 is a labile protein, comprising folded and unstructured regions that function in a synergistic manner. # Function p53 has many mechanisms of anticancer function and plays a role in apoptosis, genomic stability, and inhibition of angiogenesis. In its anti-cancer role, p53 works through several mechanisms: - It can activate DNA repair proteins when DNA has sustained damage. Thus, it may be an important factor in aging. - It can arrest growth by holding the cell cycle at the G1/S regulation point on DNA damage recognition (if it holds the cell here for long enough, the DNA repair proteins will have time to fix the damage and the cell will be allowed to continue the cell cycle). - It can initiate apoptosis (i.e., programmed cell death) if DNA damage proves to be irreparable. - It is essential for the senescence response to short telomeres. Activated p53 binds DNA and activates expression of several genes including microRNA miR-34a, WAF1/CIP1 encoding for p21 and hundreds of other down-stream genes. p21 (WAF1) binds to the G1-S/CDK (CDK4/CDK6, CDK2, and CDK1) complexes (molecules important for the G1/S transition in the cell cycle) inhibiting their activity. When p21(WAF1) is complexed with CDK2, the cell cannot continue to the next stage of cell division. A mutant p53 will no longer bind DNA in an effective way, and, as a consequence, the p21 protein will not be available to act as the "stop signal" for cell division. Studies of human embryonic stem cells (hESCs) commonly describe the nonfunctional p53-p21 axis of the G1/S checkpoint pathway with subsequent relevance for cell cycle regulation and the DNA damage response (DDR). Importantly, p21 mRNA is clearly present and upregulated after the DDR in hESCs, but p21 protein is not detectable. In this cell type, p53 activates numerous microRNAs (like miR-302a, miR-302b, miR-302c, and miR-302d) that directly inhibit the p21 expression in hESCs. Recent research has also linked the p53 and RB1 pathways, via p14ARF, raising the possibility that the pathways may regulate each other. p53 by regulating LIF has been shown to facilitate implantation in the mouse model and possibly in humans. p53 expression can be stimulated by UV light, which also causes DNA damage. In this case, p53 can initiate events leading to tanning. The p21 protein binds directly to cyclin-CDK complexes that drive forward the cell cycle and inhibits their kinase activity thereby causing cell cycle arrest to allow repair to take place. p21 can also mediate growth arrest associated with differentiation and a more permanent growth arrest associated with cellular senescence. The p21 gene contains several p53 response elements that mediate direct binding of the p53 protein, resulting in transcriptional activation of the gene encoding the p21 protein. ## Stem cells Levels of p53 play an important role in the maintenance of stem cells throughout development and the rest of human life. ### Embryonic stem cells p53 is maintained at low inactive levels in human embryonic stem cells (hESCs). This is because activation of p53 leads to rapid differentiation of hESCs. Studies have shown that knocking out p53 delays differentiation and that adding p53 causes spontaneous differentiation, showing how p53 promotes differentiation of hESCs and plays a key role in cell cycle as a differentiation regulator. When p53 becomes stabilized and activated in hESCs, it increases p21 to establish a longer G1. This typically leads to abolition of S-phase entry, which stops the cell cycle in G1, leading to differentiation. p53 also activates miR-34a and miR-145, which then repress the hESCs pluripotency factors, further instigating differentiation. Studies of human embryonic stem cells (hESCs) commonly describe the nonfunctional p53-p21 axis of the G1/S checkpoint pathway. This has subsequent relevance for cell cycle regulation and the DNA damage response (DDR). Importantly, p21 mRNA is clearly present and upregulated after the DDR in hESCs, but p21 protein is not detectable. In this cell type, p53 activates numerous microRNAs (like miR-302a, miR-302b, miR-302c, and miR-302d) that directly inhibit the p21 expression in hESCs. ### Adult stem cells In adult stem cells, p53 regulation is important for maintenance of stemness in adult stem cell niches. Mechanical signals such as hypoxia affect levels of p53 in these niche cells through the hypoxia inducible factors, HIF-1α and HIF-2α. While HIF-1α stabilizes p53, HIF-2α suppresses it. Suppression of p53 plays important roles in cancer stem cell phenotype, induced pluripotent stem cells and other stem cell roles and behaviors, such as blastema formation. Cells with decreased levels of p53 have been shown to reprogram into stem cells with a much greater efficiency that normal cells. Papers suggest that the lack of cell cycle arrest and apoptosis gives more cells the chance to be reprogrammed. Decreased levels of p53 were also shown to be a crucial aspect of blastema formation in the legs of salamanders. p53 regulation is very important in acting as a barrier between stem cells and a differentiated stem cell state, as well as a barrier between stem cells being functional and being cancerous. # Regulation p53 becomes activated in response to myriad stressors, including but not limited to DNA damage (induced by either UV, IR, or chemical agents such as hydrogen peroxide), oxidative stress, osmotic shock, ribonucleotide depletion, and deregulated oncogene expression. This activation is marked by two major events. First, the half-life of the p53 protein is increased drastically, leading to a quick accumulation of p53 in stressed cells. Second, a conformational change forces p53 to be activated as a transcription regulator in these cells. The critical event leading to the activation of p53 is the phosphorylation of its N-terminal domain. The N-terminal transcriptional activation domain contains a large number of phosphorylation sites and can be considered as the primary target for protein kinases transducing stress signals. The protein kinases that are known to target this transcriptional activation domain of p53 can be roughly divided into two groups. A first group of protein kinases belongs to the MAPK family (JNK1-3, ERK1-2, p38 MAPK), which is known to respond to several types of stress, such as membrane damage, oxidative stress, osmotic shock, heat shock, etc. A second group of protein kinases (ATR, ATM, CHK1 and CHK2, DNA-PK, CAK, TP53RK) is implicated in the genome integrity checkpoint, a molecular cascade that detects and responds to several forms of DNA damage caused by genotoxic stress. Oncogenes also stimulate p53 activation, mediated by the protein p14ARF. In unstressed cells, p53 levels are kept low through a continuous degradation of p53. A protein called Mdm2 (also called HDM2 in humans), binds to p53, preventing its action and transports it from the nucleus to the cytosol. Also Mdm2 acts as ubiquitin ligase and covalently attaches ubiquitin to p53 and thus marks p53 for degradation by the proteasome. However, ubiquitylation of p53 is reversible. MI-63 binds to MDM2 making the action of p53 again possible in situations were p53's function has become inhibited. A ubiquitin specific protease, USP7 (or HAUSP), can cleave ubiquitin off p53, thereby protecting it from proteasome-dependent degradation via the ubiquitin ligase pathway. This is one means by which p53 is stabilized in response to oncogenic insults. USP42 has also been shown to deubiquitinate p53 and may be required for the ability of p53 to respond to stress. Recent research has shown that HAUSP is mainly localized in the nucleus, though a fraction of it can be found in the cytoplasm and mitochondria. Overexpression of HAUSP results in p53 stabilization. However, depletion of HAUSP does not result to a decrease in p53 levels but rather increases p53 levels due to the fact that HAUSP binds and deubiquitinates Mdm2. It has been shown that HAUSP is a better binding partner to Mdm2 than p53 in unstressed cells. USP10 however has been shown to be located in the cytoplasm in unstressed cells and deubiquitinates cyptoplasmic p53, reversing Mdm2 ubiquitination. Following DNA damage, USP10 translocates to the nucleus and contributes to p53 stability. Also USP10 does not interact with Mdm2. Phosphorylation of the N-terminal end of p53 by the above-mentioned protein kinases disrupts Mdm2-binding. Other proteins, such as Pin1, are then recruited to p53 and induce a conformational change in p53, which prevents Mdm2-binding even more. Phosphorylation also allows for binding of transcriptional coactivators, like p300 and PCAF, which then acetylate the carboxy-terminal end of p53, exposing the DNA binding domain of p53, allowing it to activate or repress specific genes. Deacetylase enzymes, such as Sirt1 and Sirt7, can deacetylate p53, leading to an inhibition of apoptosis. Some oncogenes can also stimulate the transcription of proteins that bind to MDM2 and inhibit its activity. # Role in disease If the TP53 gene is damaged, tumor suppression is severely compromised. People who inherit only one functional copy of the TP53 gene will most likely develop tumors in early adulthood, a disorder known as Li-Fraumeni syndrome. The TP53 gene can also be modified by mutagens (chemicals, radiation, or viruses), increasing the likelihood for uncontrolled cell division. More than 50 percent of human tumors contain a mutation or deletion of the TP53 gene. Loss of p53 creates genomic instability that most often results in an aneuploidy phenotype. Increasing the amount of p53 may seem a solution for treatment of tumors or prevention of their spreading. This, however, is not a usable method of treatment, since it can cause premature aging. Restoring endogenous normal p53 function holds some promise. Research has shown that this restoration can lead to regression of certain cancer cells without damaging other cells in the process. The ways by which tumor regression occurs depends mainly on the tumor type. For example, restoration of endogenous p53 function in lymphomas may induce apoptosis, while cell growth may be reduced to normal levels. Thus, pharmacological reactivation of p53 presents itself as a viable cancer treatment option. The first commercial gene therapy, Gendicine, was approved in China in 2003 for the treatment of head and neck squamous cell carcinoma. It delivers a functional copy of the p53 gene using an engineered adenovirus. Certain pathogens can also affect the p53 protein that the TP53 gene expresses. One such example, human papillomavirus (HPV), encodes a protein, E6, which binds to the p53 protein and inactivates it. This mechanism, in synergy with the inactivation of the cell cycle regulator pRb by the HPV protein E7, allows for repeated cell division manifested clinically as warts. Certain HPV types, in particular types 16 and 18, can also lead to progression from a benign wart to low or high-grade cervical dysplasia, which are reversible forms of precancerous lesions. Persistent infection of the cervix over the years can cause irreversible changes leading to carcinoma in situ and eventually invasive cervical cancer. This results from the effects of HPV genes, particularly those encoding E6 and E7, which are the two viral oncoproteins that are preferentially retained and expressed in cervical cancers by integration of the viral DNA into the host genome. The p53 protein is continually produced and degraded in cells of healthy people, resulting in damped oscillation. The degradation of the p53 protein is associated with binding of MDM2. In a negative feedback loop, MDM2 itself is induced by the p53 protein. Mutant p53 proteins often fail to induce MDM2, causing p53 to accumulate at very high levels. Moreover, the mutant p53 protein itself can inhibit normal p53 protein levels. In some cases, single missense mutations in p53 have been shown to disrupt p53 stability and function. Suppression of p53 in human breast cancer cells is shown to lead to increased CXCR5 chemokine receptor gene expression and activated cell migration in response to chemokine CXCL13. One study found that p53 and Myc proteins were key to the survival of Chronic Myeloid Leukaemia (CML) cells. Targeting p53 and Myc proteins with drugs gave positive results on mice with CML. # Experimental analysis of p53 mutations Most p53 mutations are detected by DNA sequencing. However, it is known that single missense mutations can have a large spectrum from rather mild to very severe functional affects. The large spectrum of cancer phenotypes due to mutations in the TP53 gene is also supported by the fact that different isoforms of p53 proteins have different cellular mechanisms for prevention against cancer. Mutations in TP53 can give rise to different isoforms, preventing their overall functionality in different cellular mechanisms and thereby extending the cancer phenotype from mild to severe. Recents studies show that p53 isoforms are differentially expressed in different human tissues, and the loss-of-function or gain-of-function mutations within the isoforms can cause tissue-specific cancer or provides cancer stem cell potential in different tissues. TP53 mutation also hits energy metabolism and increases glycolysis in breast cancer cells. The dynamics of p53 proteins, along with its antagonist Mdm2, indicate that the levels of p53, in units of concentration, oscillate as a function of time. This "damped" oscillation is both clinically documented and mathematically modelled. Mathematical models also indicate that the p53 concentration oscillates much faster once teratogens, such as double-stranded breaks (DSB) or UV radiation, are introduced to the system. This supports and models the current understanding of p53 dynamics, where DNA damage induces p53 activation (see p53 regulation for more information). Current models can also be useful for modelling the mutations in p53 isoforms and their effects on p53 oscillation, thereby promoting de novo tissue-specific pharmacological drug discovery. # Discovery p53 was identified in 1979 by Lionel Crawford, David P. Lane, Arnold Levine, and Lloyd Old, working at Imperial Cancer Research Fund (UK) Princeton University/UMDNJ (Cancer Institute of New Jersey), and Memorial Sloan-Kettering Cancer Center, respectively. It had been hypothesized to exist before as the target of the SV40 virus, a strain that induced development of tumors. The TP53 gene from the mouse was first cloned by Peter Chumakov of the Russian Academy of Sciences in 1982, and independently in 1983 by Moshe Oren in collaboration with David Givol (Weizmann Institute of Science). The human TP53 gene was cloned in 1984 and the full length clone in 1985. It was initially presumed to be an oncogene due to the use of mutated cDNA following purification of tumor cell mRNA. Its role as a tumor suppressor gene was revealed in 1989 by Bert Vogelstein at the Johns Hopkins School of Medicine and Arnold Levine at Princeton University. Warren Maltzman, of the Waksman Institute of Rutgers University first demonstrated that TP53 was responsive to DNA damage in the form of ultraviolet radiation. In a series of publications in 1991–92, Michael Kastan of Johns Hopkins University, reported that TP53 was a critical part of a signal transduction pathway that helped cells respond to DNA damage. In 1993, p53 was voted molecule of the year by Science magazine. # Isoforms As with 95% of human genes, TP53 encodes more than one protein. In 2005 several isoforms were discovered and until now, 12 human p53 isoforms were identified (p53α, p53β, p53γ, ∆40p53α, ∆40p53β, ∆40p53γ, ∆133p53α, ∆133p53β, ∆133p53γ, ∆160p53α, ∆160p53β, ∆160p53γ). Furthermore, p53 isoforms are expressed in a tissue dependent manner and p53α is never expressed alone. The full length p53 isoform proteins can be subdivided into different protein domains. Starting from the N-terminus, there are first the amino-terminal transactivation domains (TAD 1, TAD 2), which are needed to induce a subset of p53 target genes. This domain is followed by the Proline rich domain (PXXP), whereby the motif PXXP is repeated (P is a Proline and X can be any amino acid). It is required among others for p53 mediated apoptosis. Some isoforms lack the Proline rich domain, such as Δ133p53β,γ and Δ160p53α,β,γ; hence some isoforms of p53 are not mediating apoptosis, emphasizing the diversifying roles of the TP53 gene. Afterwards there is the DNA binding domain (DBD), which enables the proteins to sequence specific binding. The carboxyl terminal domain completes the protein. It includes the nuclear localization signal (NLS), the nuclear export signal (NES) and the oligomerisation domain (OD). The NLS and NES are responsible for the subcellular regulation of p53. Through the OD, p53 can form a tetramer and then bind to DNA. Among the isoforms, some domains can be missing, but all of them share most of the highly conserved DNA-binding domain. The isoforms are formed by different mechanisms. The beta and the gamma isoforms are generated by multiple splicing of intron 9, which leads to a different C-terminus. Furthermore, the usage of an internal promoter in intron 4 causes the ∆133 and ∆160 isoforms, which lack the TAD domain and a part of the DBD. Moreover, alternative initiation of translation at codon 40 or 160 bear the ∆40p53 and ∆160p53 isoforms. Due to the isoformic nature of p53 proteins, there have been several sources of evidence showing that mutations within the TP53 gene giving rise to mutated isoforms are causative agents of various cancer phenotypes, from mild to severe, due to single mutation in the TP53 gene (refer to section Experimental analysis of p53 mutations for more details). # Interactions p53 has been shown to interact with: - AIMP2, - ANKRD2, - APTX, - ATM, - ATR, - ATF3, - AURKA, - BAK1, - BARD1, - BLM, - BRCA1, - BRCA2, - BRCC3, - BRE, - CEBPZ, - CDC14A, - Cdk1, - CFLAR, - CHEK1, - CCNG1, - CREBBP, - CREB1, - Cyclin H, - CDK7, - DNA-PKcs, - E4F1, - EFEMP2, - EIF2AK2, - ELL, - EP300, - ERCC6, - GNL3, - GPS2, - GSK3B, - HSP90AA1, - HIF1A, - HIPK1, - HIPK2, - HMGB1, - HSPA9, - Huntingtin, - ING1, - ING4, - ING5, - IκBα, - KPNB1, - LMO3, - Mdm2, - MDM4, - MED1, - MAPK9, - MNAT1, - NDN, - NCL, - NUMB, - NF-κB, - P16, - PARC, - PARP1, - PIAS1, - CDC14B, - PIN1, - PLAGL1, - PLK3, - PRKRA, - PHB, - PML, - PSME3, - PTEN, - PTK2, - PTTG1, - RAD51, - RCHY1, - RELA, - Reprimo - RPA1, - RPL11, - S100B, - SUMO1, - SMARCA4, - SMARCB1, - SMN1, - STAT3, - TBP, - TFAP2A, - TFDP1, - TIGAR, - TOP1, - TOP2A, - TP53BP1, - TP53BP2, - TOP2B, - TP53INP1, - TSG101, - UBE2A, - UBE2I, - UBC, - USP7, - WRN, - WWOX, - XPB, - YBX1, - YPEL3, - YWHAZ, - Zif268, - ZNF148. - SIRT1. # Peto's paradox Peto's Paradox is the observation, due to Richard Peto, that at the species level, the incidence of cancer does not appear to correlate with the number of cells in an organism. For example, the incidence of cancer in humans is much higher than the incidence of cancer in whales. This is despite the fact that a whale has many more cells than a human. If the probability of carcinogenesis were constant across cells, one would expect whales to have a higher incidence of cancer than humans. The same is true of elephants. In October 2015, two independent studies showed that elephants have 20 copies of a tumor suppressor gene TP53 in their genome, where humans and other mammals have only one, thus providing a possible solution to the paradox.

TP53 Template:Hatlink Tumor protein p53, also known as p53, cellular tumor antigen p53 (UniProt name), phosphoprotein p53, tumor suppressor p53, antigen NY-CO-13, or transformation-related protein 53 (TRP53), is any isoform of a protein encoded by homologous genes in various organisms, such as TP53 (humans) and Trp53 (mice). This homolog (originally thought to be, and often spoken of as, a single protein) is crucial in multicellular organisms, where it prevents cancer formation, thus, functions as a tumor suppressor.[1] As such, p53 has been described as "the guardian of the genome" because of its role in conserving stability by preventing genome mutation.[2] Hence TP53 is classified as a tumor suppressor gene.[3][4][5][6][7] (Italics are used to denote the TP53 gene name and distinguish it from the protein it encodes.) The name p53 was given in 1979 describing the apparent molecular mass; SDS-PAGE analysis indicates that it is a 53-kilodalton (kDa) protein. However, the actual mass of the full-length p53 protein (p53α) based on the sum of masses of the amino acid residues is only 43.7 kDa. This difference is due to the high number of proline residues in the protein, which slow its migration on SDS-PAGE, thus making it appear heavier than it actually is.[8] In addition to the full-length protein, the human TP53 gene encodes at least 15 protein isoforms, ranging in size from 3.5 to 43.7 kDa. All these p53 proteins are called the p53 isoforms.[1] The TP53 gene is the most frequently mutated gene (>50%) in human cancer, indicating that the TP53 gene plays a crucial role in preventing cancer formation.[1] TP53 gene encodes proteins that bind to DNA and regulate gene expression to prevent mutations of the genome.[9] # Gene In humans, the TP53 gene is located on the short arm of chromosome 17 (17p13.1).[3][4][5][6] The gene spans 20 kb, with a non-coding exon 1 and a very long first intron of 10 kb. The coding sequence contains five regions showing a high degree of conservation in vertebrates, predominantly in exons 2, 5, 6, 7 and 8, but the sequences found in invertebrates show only distant resemblance to mammalian TP53.[10] TP53 orthologs[11] have been identified in most mammals for which complete genome data are available. In humans, a common polymorphism involves the substitution of an arginine for a proline at codon position 72. Many studies have investigated a genetic link between this variation and cancer susceptibility; however, the results have been controversial. For instance, a meta-analysis from 2009 failed to show a link for cervical cancer.[12] A 2011 study found that the TP53 proline mutation did have a profound effect on pancreatic cancer risk among males.[13] A study of Arab women found that proline homozygosity at TP53 codon 72 is associated with a decreased risk for breast cancer.[14] One study suggested that TP53 codon 72 polymorphisms, MDM2 SNP309, and A2164G may collectively be associated with non-oropharyngeal cancer susceptibility and that MDM2 SNP309 in combination with TP53 codon 72 may accelerate the development of non-oropharyngeal cancer in women.[15] A 2011 study found that TP53 codon 72 polymorphism was associated with an increased risk of lung cancer.[16] Meta-analyses from 2011 found no significant associations between TP53 codon 72 polymorphisms and both colorectal cancer risk[17] and endometrial cancer risk.[18] A 2011 study of a Brazilian birth cohort found an association between the non mutant arginine TP53 and individuals without a family history of cancer.[19] Another 2011 study found that the p53 homozygous (Pro/Pro) genotype was associated with a significantly increased risk for renal cell carcinoma.[20] # Structure - an acidic N-terminus transcription-activation domain (TAD), also known as activation domain 1 (AD1), which activates transcription factors. The N-terminus contains two complementary transcriptional activation domains, with a major one at residues 1–42 and a minor one at residues 55–75, specifically involved in the regulation of several pro-apoptotic genes.[21] - activation domain 2 (AD2) important for apoptotic activity: residues 43-63. - proline rich domain important for the apoptotic activity of p53 by nuclear exportation via MAPK: residues 64-92. - central DNA-binding core domain (DBD). Contains one zinc atom and several arginine amino acids: residues 102-292. This region is responsible for binding the p53 co-repressor LMO3.[22] - nuclear localization signaling domain, residues 316-325. - homo-oligomerisation domain (OD): residues 307-355. Tetramerization is essential for the activity of p53 in vivo. - C-terminal involved in downregulation of DNA binding of the central domain: residues 356-393.[23] A tandem of nine-amino-acid transactivation domains (9aaTAD) was identified in the AD1 and AD2 regions of transcription factor p53.[24] KO mutations and position for p53 interaction with TFIID are listed below:[25] The competence of the p53 transactivation domains 9aaTAD to activate transcription as small peptides was reported.[26] File:Piskacek p53b.jpg p53 transactivation Piskacek M, Havelka M, Rezacova M, Knight A. "The 9aaTAD Transactivation Domains: From Gal4 to p53". PLoS ONE. 11: e0162842. doi:10.1371/journal.pone.0162842. PMC 5019370. PMID 27618436. 9aaTADs mediate p53 interaction with general coactivators – TAF9, CBP/p300 (all four domains KIX, TAZ1, TAZ2 and IBiD), GCN5 and PC4, regulatory protein MDM2 and replication protein A (RPA).[24] File:Piskacek p53a.jpg p53 conversion Piskacek M, Havelka M, Rezacova M, Knight A. "The 9aaTAD Transactivation Domains: From Gal4 to p53". PLoS ONE. 11: e0162842. doi:10.1371/journal.pone.0162842. PMC 5019370. PMID 27618436. Mutations that deactivate p53 in cancer usually occur in the DBD. Most of these mutations destroy the ability of the protein to bind to its target DNA sequences, and thus prevents transcriptional activation of these genes. As such, mutations in the DBD are recessive loss-of-function mutations. Molecules of p53 with mutations in the OD dimerise with wild-type p53, and prevent them from activating transcription. Therefore, OD mutations have a dominant negative effect on the function of p53. Wild-type p53 is a labile protein, comprising folded and unstructured regions that function in a synergistic manner.[27] # Function p53 has many mechanisms of anticancer function and plays a role in apoptosis, genomic stability, and inhibition of angiogenesis. In its anti-cancer role, p53 works through several mechanisms: - It can activate DNA repair proteins when DNA has sustained damage. Thus, it may be an important factor in aging.[28] - It can arrest growth by holding the cell cycle at the G1/S regulation point on DNA damage recognition (if it holds the cell here for long enough, the DNA repair proteins will have time to fix the damage and the cell will be allowed to continue the cell cycle). - It can initiate apoptosis (i.e., programmed cell death) if DNA damage proves to be irreparable. - It is essential for the senescence response to short telomeres. Activated p53 binds DNA and activates expression of several genes including microRNA miR-34a,[29] WAF1/CIP1 encoding for p21 and hundreds of other down-stream genes. p21 (WAF1) binds to the G1-S/CDK (CDK4/CDK6, CDK2, and CDK1) complexes (molecules important for the G1/S transition in the cell cycle) inhibiting their activity. When p21(WAF1) is complexed with CDK2, the cell cannot continue to the next stage of cell division. A mutant p53 will no longer bind DNA in an effective way, and, as a consequence, the p21 protein will not be available to act as the "stop signal" for cell division.[30] Studies of human embryonic stem cells (hESCs) commonly describe the nonfunctional p53-p21 axis of the G1/S checkpoint pathway with subsequent relevance for cell cycle regulation and the DNA damage response (DDR). Importantly, p21 mRNA is clearly present and upregulated after the DDR in hESCs, but p21 protein is not detectable. In this cell type, p53 activates numerous microRNAs (like miR-302a, miR-302b, miR-302c, and miR-302d) that directly inhibit the p21 expression in hESCs.[31] Recent research has also linked the p53 and RB1 pathways, via p14ARF, raising the possibility that the pathways may regulate each other.[32] p53 by regulating LIF has been shown to facilitate implantation in the mouse model and possibly in humans.[33] p53 expression can be stimulated by UV light, which also causes DNA damage. In this case, p53 can initiate events leading to tanning.[34][35] The p21 protein binds directly to cyclin-CDK complexes that drive forward the cell cycle and inhibits their kinase activity thereby causing cell cycle arrest to allow repair to take place. p21 can also mediate growth arrest associated with differentiation and a more permanent growth arrest associated with cellular senescence. The p21 gene contains several p53 response elements that mediate direct binding of the p53 protein, resulting in transcriptional activation of the gene encoding the p21 protein. ## Stem cells Levels of p53 play an important role in the maintenance of stem cells throughout development and the rest of human life. ### Embryonic stem cells p53 is maintained at low inactive levels in human embryonic stem cells (hESCs).[36] This is because activation of p53 leads to rapid differentiation of hESCs.[37] Studies have shown that knocking out p53 delays differentiation and that adding p53 causes spontaneous differentiation, showing how p53 promotes differentiation of hESCs and plays a key role in cell cycle as a differentiation regulator. When p53 becomes stabilized and activated in hESCs, it increases p21 to establish a longer G1. This typically leads to abolition of S-phase entry, which stops the cell cycle in G1, leading to differentiation. p53 also activates miR-34a and miR-145, which then repress the hESCs pluripotency factors, further instigating differentiation.[36] Studies of human embryonic stem cells (hESCs) commonly describe the nonfunctional p53-p21 axis of the G1/S checkpoint pathway. This has subsequent relevance for cell cycle regulation and the DNA damage response (DDR). Importantly, p21 mRNA is clearly present and upregulated after the DDR in hESCs, but p21 protein is not detectable. In this cell type, p53 activates numerous microRNAs (like miR-302a, miR-302b, miR-302c, and miR-302d) that directly inhibit the p21 expression in hESCs.[31] ### Adult stem cells In adult stem cells, p53 regulation is important for maintenance of stemness in adult stem cell niches. Mechanical signals such as hypoxia affect levels of p53 in these niche cells through the hypoxia inducible factors, HIF-1α and HIF-2α. While HIF-1α stabilizes p53, HIF-2α suppresses it.[38] Suppression of p53 plays important roles in cancer stem cell phenotype, induced pluripotent stem cells and other stem cell roles and behaviors, such as blastema formation. Cells with decreased levels of p53 have been shown to reprogram into stem cells with a much greater efficiency that normal cells.[39][40] Papers suggest that the lack of cell cycle arrest and apoptosis gives more cells the chance to be reprogrammed. Decreased levels of p53 were also shown to be a crucial aspect of blastema formation in the legs of salamanders.[41] p53 regulation is very important in acting as a barrier between stem cells and a differentiated stem cell state, as well as a barrier between stem cells being functional and being cancerous.[42] # Regulation p53 becomes activated in response to myriad stressors, including but not limited to DNA damage (induced by either UV, IR, or chemical agents such as hydrogen peroxide), oxidative stress,[43] osmotic shock, ribonucleotide depletion, and deregulated oncogene expression. This activation is marked by two major events. First, the half-life of the p53 protein is increased drastically, leading to a quick accumulation of p53 in stressed cells. Second, a conformational change forces p53 to be activated as a transcription regulator in these cells. The critical event leading to the activation of p53 is the phosphorylation of its N-terminal domain. The N-terminal transcriptional activation domain contains a large number of phosphorylation sites and can be considered as the primary target for protein kinases transducing stress signals. The protein kinases that are known to target this transcriptional activation domain of p53 can be roughly divided into two groups. A first group of protein kinases belongs to the MAPK family (JNK1-3, ERK1-2, p38 MAPK), which is known to respond to several types of stress, such as membrane damage, oxidative stress, osmotic shock, heat shock, etc. A second group of protein kinases (ATR, ATM, CHK1 and CHK2, DNA-PK, CAK, TP53RK) is implicated in the genome integrity checkpoint, a molecular cascade that detects and responds to several forms of DNA damage caused by genotoxic stress. Oncogenes also stimulate p53 activation, mediated by the protein p14ARF. In unstressed cells, p53 levels are kept low through a continuous degradation of p53. A protein called Mdm2 (also called HDM2 in humans), binds to p53, preventing its action and transports it from the nucleus to the cytosol. Also Mdm2 acts as ubiquitin ligase and covalently attaches ubiquitin to p53 and thus marks p53 for degradation by the proteasome. However, ubiquitylation of p53 is reversible. MI-63 binds to MDM2 making the action of p53 again possible in situations were p53's function has become inhibited.[44] A ubiquitin specific protease, USP7 (or HAUSP), can cleave ubiquitin off p53, thereby protecting it from proteasome-dependent degradation via the ubiquitin ligase pathway. This is one means by which p53 is stabilized in response to oncogenic insults. USP42 has also been shown to deubiquitinate p53 and may be required for the ability of p53 to respond to stress.[45] Recent research has shown that HAUSP is mainly localized in the nucleus, though a fraction of it can be found in the cytoplasm and mitochondria. Overexpression of HAUSP results in p53 stabilization. However, depletion of HAUSP does not result to a decrease in p53 levels but rather increases p53 levels due to the fact that HAUSP binds and deubiquitinates Mdm2. It has been shown that HAUSP is a better binding partner to Mdm2 than p53 in unstressed cells. USP10 however has been shown to be located in the cytoplasm in unstressed cells and deubiquitinates cyptoplasmic p53, reversing Mdm2 ubiquitination. Following DNA damage, USP10 translocates to the nucleus and contributes to p53 stability. Also USP10 does not interact with Mdm2.[46] Phosphorylation of the N-terminal end of p53 by the above-mentioned protein kinases disrupts Mdm2-binding. Other proteins, such as Pin1, are then recruited to p53 and induce a conformational change in p53, which prevents Mdm2-binding even more. Phosphorylation also allows for binding of transcriptional coactivators, like p300 and PCAF, which then acetylate the carboxy-terminal end of p53, exposing the DNA binding domain of p53, allowing it to activate or repress specific genes. Deacetylase enzymes, such as Sirt1 and Sirt7, can deacetylate p53, leading to an inhibition of apoptosis.[47] Some oncogenes can also stimulate the transcription of proteins that bind to MDM2 and inhibit its activity. # Role in disease If the TP53 gene is damaged, tumor suppression is severely compromised. People who inherit only one functional copy of the TP53 gene will most likely develop tumors in early adulthood, a disorder known as Li-Fraumeni syndrome. The TP53 gene can also be modified by mutagens (chemicals, radiation, or viruses), increasing the likelihood for uncontrolled cell division. More than 50 percent of human tumors contain a mutation or deletion of the TP53 gene.[48] Loss of p53 creates genomic instability that most often results in an aneuploidy phenotype.[49] Increasing the amount of p53 may seem a solution for treatment of tumors or prevention of their spreading. This, however, is not a usable method of treatment, since it can cause premature aging.[50] Restoring endogenous normal p53 function holds some promise. Research has shown that this restoration can lead to regression of certain cancer cells without damaging other cells in the process. The ways by which tumor regression occurs depends mainly on the tumor type. For example, restoration of endogenous p53 function in lymphomas may induce apoptosis, while cell growth may be reduced to normal levels. Thus, pharmacological reactivation of p53 presents itself as a viable cancer treatment option.[51][52] The first commercial gene therapy, Gendicine, was approved in China in 2003 for the treatment of head and neck squamous cell carcinoma. It delivers a functional copy of the p53 gene using an engineered adenovirus.[53] Certain pathogens can also affect the p53 protein that the TP53 gene expresses. One such example, human papillomavirus (HPV), encodes a protein, E6, which binds to the p53 protein and inactivates it. This mechanism, in synergy with the inactivation of the cell cycle regulator pRb by the HPV protein E7, allows for repeated cell division manifested clinically as warts. Certain HPV types, in particular types 16 and 18, can also lead to progression from a benign wart to low or high-grade cervical dysplasia, which are reversible forms of precancerous lesions. Persistent infection of the cervix over the years can cause irreversible changes leading to carcinoma in situ and eventually invasive cervical cancer. This results from the effects of HPV genes, particularly those encoding E6 and E7, which are the two viral oncoproteins that are preferentially retained and expressed in cervical cancers by integration of the viral DNA into the host genome.[54] The p53 protein is continually produced and degraded in cells of healthy people, resulting in damped oscillation. The degradation of the p53 protein is associated with binding of MDM2. In a negative feedback loop, MDM2 itself is induced by the p53 protein. Mutant p53 proteins often fail to induce MDM2, causing p53 to accumulate at very high levels. Moreover, the mutant p53 protein itself can inhibit normal p53 protein levels. In some cases, single missense mutations in p53 have been shown to disrupt p53 stability and function.[55] Suppression of p53 in human breast cancer cells is shown to lead to increased CXCR5 chemokine receptor gene expression and activated cell migration in response to chemokine CXCL13.[56] One study found that p53 and Myc proteins were key to the survival of Chronic Myeloid Leukaemia (CML) cells. Targeting p53 and Myc proteins with drugs gave positive results on mice with CML.[57][58] # Experimental analysis of p53 mutations Most p53 mutations are detected by DNA sequencing. However, it is known that single missense mutations can have a large spectrum from rather mild to very severe functional affects.[55] The large spectrum of cancer phenotypes due to mutations in the TP53 gene is also supported by the fact that different isoforms of p53 proteins have different cellular mechanisms for prevention against cancer. Mutations in TP53 can give rise to different isoforms, preventing their overall functionality in different cellular mechanisms and thereby extending the cancer phenotype from mild to severe. Recents studies show that p53 isoforms are differentially expressed in different human tissues, and the loss-of-function or gain-of-function mutations within the isoforms can cause tissue-specific cancer or provides cancer stem cell potential in different tissues.[7][59][60][61] TP53 mutation also hits energy metabolism and increases glycolysis in breast cancer cells.[62] The dynamics of p53 proteins, along with its antagonist Mdm2, indicate that the levels of p53, in units of concentration, oscillate as a function of time. This "damped" oscillation is both clinically documented [63] and mathematically modelled.[64][65] Mathematical models also indicate that the p53 concentration oscillates much faster once teratogens, such as double-stranded breaks (DSB) or UV radiation, are introduced to the system. This supports and models the current understanding of p53 dynamics, where DNA damage induces p53 activation (see p53 regulation for more information). Current models can also be useful for modelling the mutations in p53 isoforms and their effects on p53 oscillation, thereby promoting de novo tissue-specific pharmacological drug discovery. # Discovery p53 was identified in 1979 by Lionel Crawford, David P. Lane, Arnold Levine, and Lloyd Old, working at Imperial Cancer Research Fund (UK) Princeton University/UMDNJ (Cancer Institute of New Jersey), and Memorial Sloan-Kettering Cancer Center, respectively. It had been hypothesized to exist before as the target of the SV40 virus, a strain that induced development of tumors. The TP53 gene from the mouse was first cloned by Peter Chumakov of the Russian Academy of Sciences in 1982,[66] and independently in 1983 by Moshe Oren in collaboration with David Givol (Weizmann Institute of Science).[67][68] The human TP53 gene was cloned in 1984[3] and the full length clone in 1985.[69] It was initially presumed to be an oncogene due to the use of mutated cDNA following purification of tumor cell mRNA. Its role as a tumor suppressor gene was revealed in 1989 by Bert Vogelstein at the Johns Hopkins School of Medicine and Arnold Levine at Princeton University.[70][71] Warren Maltzman, of the Waksman Institute of Rutgers University first demonstrated that TP53 was responsive to DNA damage in the form of ultraviolet radiation.[72] In a series of publications in 1991–92, Michael Kastan of Johns Hopkins University, reported that TP53 was a critical part of a signal transduction pathway that helped cells respond to DNA damage.[73] In 1993, p53 was voted molecule of the year by Science magazine.[74] # Isoforms As with 95% of human genes, TP53 encodes more than one protein. In 2005 several isoforms were discovered and until now, 12 human p53 isoforms were identified (p53α, p53β, p53γ, ∆40p53α, ∆40p53β, ∆40p53γ, ∆133p53α, ∆133p53β, ∆133p53γ, ∆160p53α, ∆160p53β, ∆160p53γ). Furthermore, p53 isoforms are expressed in a tissue dependent manner and p53α is never expressed alone.[7] The full length p53 isoform proteins can be subdivided into different protein domains. Starting from the N-terminus, there are first the amino-terminal transactivation domains (TAD 1, TAD 2), which are needed to induce a subset of p53 target genes. This domain is followed by the Proline rich domain (PXXP), whereby the motif PXXP is repeated (P is a Proline and X can be any amino acid). It is required among others for p53 mediated apoptosis.[75] Some isoforms lack the Proline rich domain, such as Δ133p53β,γ and Δ160p53α,β,γ; hence some isoforms of p53 are not mediating apoptosis, emphasizing the diversifying roles of the TP53 gene.[59] Afterwards there is the DNA binding domain (DBD), which enables the proteins to sequence specific binding. The carboxyl terminal domain completes the protein. It includes the nuclear localization signal (NLS), the nuclear export signal (NES) and the oligomerisation domain (OD). The NLS and NES are responsible for the subcellular regulation of p53. Through the OD, p53 can form a tetramer and then bind to DNA. Among the isoforms, some domains can be missing, but all of them share most of the highly conserved DNA-binding domain. The isoforms are formed by different mechanisms. The beta and the gamma isoforms are generated by multiple splicing of intron 9, which leads to a different C-terminus. Furthermore, the usage of an internal promoter in intron 4 causes the ∆133 and ∆160 isoforms, which lack the TAD domain and a part of the DBD. Moreover, alternative initiation of translation at codon 40 or 160 bear the ∆40p53 and ∆160p53 isoforms.[7] Due to the isoformic nature of p53 proteins, there have been several sources of evidence showing that mutations within the TP53 gene giving rise to mutated isoforms are causative agents of various cancer phenotypes, from mild to severe, due to single mutation in the TP53 gene (refer to section Experimental analysis of p53 mutations for more details). # Interactions p53 has been shown to interact with: - AIMP2,[76] - ANKRD2,[77] - APTX,[78] - ATM,[79][80][81][82][83] - ATR,[79][80] - ATF3,[84][85] - AURKA,[86] - BAK1,[87] - BARD1,[88] - BLM,[89][90][91][92] - BRCA1,[88][93][94][95][96] - BRCA2,[88][97] - BRCC3,[88] - BRE,[88] - CEBPZ,[98] - CDC14A,[99] - Cdk1,[100][101] - CFLAR,[102] - CHEK1,[89][103][104] - CCNG1,[105] - CREBBP,[106][107][108] - CREB1,[108] - Cyclin H,[109] - CDK7,[109][110] - DNA-PKcs,[80][103][111] - E4F1,[112][113] - EFEMP2,[114] - EIF2AK2,[115] - ELL,[116] - EP300,[107][117][118][119] - ERCC6,[120][121] - GNL3,[122] - GPS2,[123] - GSK3B,[124] - HSP90AA1,[125][126][127] - HIF1A,[128][129][130][131] - HIPK1,[132] - HIPK2,[133][134] - HMGB1,[135][136] - HSPA9,[137] - Huntingtin,[138] - ING1,[139][140] - ING4,[141][142] - ING5,[141] - IκBα,[143] - KPNB1,[125] - LMO3,[22] - Mdm2,[106][144][145][146] - MDM4,[147][148] - MED1,[149][150] - MAPK9,[151][152] - MNAT1,[110] - NDN,[153] - NCL,[154] - NUMB,[155] - NF-κB,[156] - P16,[112][146][157] - PARC,[158] - PARP1,[78][159] - PIAS1,[114][160] - CDC14B,[99] - PIN1,[161][162] - PLAGL1,[163] - PLK3,[164][165] - PRKRA,[166] - PHB,[167] - PML,[144][168][169] - PSME3,[170] - PTEN,[145] - PTK2,[171] - PTTG1,[172] - RAD51,[88][173][174] - RCHY1,[175][176] - RELA,[156] - Reprimo[177] - RPA1,[178][179] - RPL11,[157] - S100B,[180] - SUMO1,[181][182] - SMARCA4,[183] - SMARCB1,[183] - SMN1,[184] - STAT3,[156] - TBP,[185][186] - TFAP2A,[187] - TFDP1,[188] - TIGAR,[189] - TOP1,[190][191] - TOP2A,[192] - TP53BP1,[89][193][194][195][196][197][198] - TP53BP2,[198][199] - TOP2B,[192] - TP53INP1,[200][201] - TSG101,[202] - UBE2A,[203] - UBE2I,[114][181][204][205] - UBC,[76][170][182][206][207][208][209][210] - USP7,[211] - WRN,[92][212] - WWOX,[213] - XPB,[120] - YBX1,[77][214] - YPEL3,[215] - YWHAZ,[216] - Zif268,[217] - ZNF148.[218] - SIRT1.[219] # Peto's paradox Peto's Paradox is the observation, due to Richard Peto, that at the species level, the incidence of cancer does not appear to correlate with the number of cells in an organism.[220] For example, the incidence of cancer in humans is much higher than the incidence of cancer in whales.[221] This is despite the fact that a whale has many more cells than a human. If the probability of carcinogenesis were constant across cells, one would expect whales to have a higher incidence of cancer than humans. The same is true of elephants. In October 2015, two independent studies showed that elephants have 20 copies of a tumor suppressor gene TP53 in their genome, where humans and other mammals have only one, thus providing a possible solution to the paradox.[222]

https://www.wikidoc.org/index.php/TP53