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Rnd1 Rnd1 is a small (~21 kDa) signaling G protein (to be specific, a GTPase), and is a member of the Rnd subgroup of the Rho family of GTPases.It is encoded by the gene RND1. It contributes to regulating the organization of the actin cytoskeleton in response to extracellular growth factors (Nobes et al.,1998). # Interactions Rnd1 has been shown to interact with GRB7, PLXNB1, PDE6D, ARHGAP5 and UBXD5.

Rnd2 Rnd2 is a small (~21 kDa) signaling G protein (to be specific, a GTPase), and is a member of the Rnd subgroup of the Rho family of GTPases.It is encoded by the gene RND2. # Function It contributes to regulating the organization of the actin cytoskeleton in response to extracellular growth factors (Nobes et al.,1998). This particular family member has been implicated in the regulation of neuronal morphology and endosomal trafficking. # Clinical significance The gene localizes to chromosome 17 and is the centromeric neighbor of the breast-ovarian cancer susceptibility gene BRCA1. # Interactions Rnd2 has been shown to interact with: - ARHGAP5, - RACGAP1, and - UBXD5.

Rnd3 Rnd3 is a small (~21 kDa) signaling G protein (to be specific, a GTPase), and is a member of the Rnd subgroup of the Rho family of GTPases.It is encoded by the gene RND3. Like other members of the Rho family of Ras-related GTPases it regulates the organization of the actin cytoskeleton in response to extracellular growth factors. # Regulation Like Ras, Rho family members appear to cycle between an inactive GDP-bound form and an active GTP-bound form.Three major regulators of Rho activity have been identified: RhoGDIs, which interact with the GDP-bound Rho proteins to keep them in a resting complex (see MIM 601925); GEFs, which promote GDP/GTP exchange leading to activation of Rho proteins (see MIM 601855); and GAPs, which stimulate GTP hydrolysis and return the activated Rho protein to its inactive form (see MIM 602680) (Nobes et al.,1998). # Interactions Rnd3 has been shown to interact with ARHGAP5 and UBXD5.

RNF4 RING finger protein 4 is a protein that in humans is encoded by the RNF4 gene. The protein encoded by this gene contains a RING finger domain and acts as a transcription factor.This protein has been shown to interact with, and inhibit the activity of, TRPS1, a transcription suppressor of GATA-mediated transcription.Transcription repressor ZNF278/PATZ1 is found to interact with this protein, and thus reduce the enhancement of androgen receptor-dependent transcription mediated by this protein.Studies of the mouse and rat counterparts suggested a role of this protein in spermatogenesis. # Interactions RNF4 has been shown to interact with TCF20, PATZ1 and Androgen receptor.

RNF8 E3 ubiquitin-protein ligase RNF8 is an enzyme that in humans is encoded by the RNF8 gene. RNF8 has activity both in immune system functions and in DNA repair. # Function The protein encoded by this gene contains a RING finger motif and an FHA domain.This protein has been shown to interact with several class II ubiquitin-conjugating enzymes (E2), including UBE2E1/UBCH6, UBE2E2, and UBE2E3, and may act as a ubiquitin ligase (E3) in the ubiquitination of certain nuclear proteins.Alternatively spliced transcript variants encoding distinct isoforms have been reported. RNF8 promotes repair of DNA damage through three DNA repair pathways: homologous recombinational repair (HRR), non-homologous end joining (NHEJ), and nucleotide excision repair (NER). DNA damage is considered to be the primary cause of cancer, and deficiency in DNA repair can cause mutations leading to cancer. A deficiency in RNF8 predisposes mice to cancer. # Chromatin remodeling After the occurrence of a double-strand break in DNA, the chromatin needs to be relaxed to allow DNA repair, either by HRR or by NHEJ. There are two pathways that result in chromatin relaxation, one initiated by PARP1 and one initiated by γH2AX (the phosphorylated form of the H2AX protein) (see Chromatin remodeling). Chromatin remodeling initiated by γH2AX depends on RNF8, as described below. The histone variant H2AX constitutes about 10% of the H2A histones in human chromatin. At the site of a DNA double-strand break, the extent of chromatin with phosphorylated γH2AX is about two million base pairs. γH2AX does not, by itself, cause chromatin decondensation, but within seconds of irradiation the protein “Mediator of the DNA damage checkpoint 1” (MDC1) specifically attaches to γH2AX. This is accompanied by simultaneous accumulation of RNF8 protein and the DNA repair protein NBS1 which bind to MDC1. RNF8 mediates extensive chromatin decondensation through its subsequent interaction with CHD4 protein, a component of the nucleosome remodeling and deacetylase complex NuRD. # RNF8 in Homologous Recombinational Repair DNA end resection is a pivotal step in HRR repair that produces 3’ overhangs that provide a platform to recruit proteins involved in HRR repair. The MRN complex, consisting of Mre11, Rad50 and NBS1, carries out the initial steps of this end resection. RNF8 ubiquitinates NBS1 (both before and after DNA damage occurs), and this ubiquitination is required for effective homologous recombinational repair. Ubiquitination of NBS1 by RNF8 is, however, not required for the role of NBS1 in another DNA repair process, the error-prone microhomology-mediated end joining DNA repair. RNF8 appears to have other roles in HRR as well. RNF8, acting as a ubiquitin ligase, mono-ubiquitinates γH2AX to tether DNA repair molecules at DNA lesions. In particular, RNF8 activity is required to recruit BRCA1 for homologous recombination repair. # RNF8 in Non-Homologous End Joining Ku protein is a dimeric protein complex, a heterodimer of two polypeptides, Ku70 and Ku80. Ku protein forms a ring structure. An early step in non-homologous end joining DNA repair of a double-strand break is the slipping of a Ku protein (with its ring protein structure) over each end of the broken DNA. The two Ku proteins, one on each broken end, bind to each other and form a bridge. This protects the DNA ends and forms a platform for further DNA repair enzymes to operate. After the broken ends are rejoined, the two Ku proteins still encircle the now intact DNA and can no longer slip off an end. The Ku proteins must be removed or they cause loss of cell viability. The removal of Ku protein is performed either by RNF8 ubiquitination of Ku80, allowing it to be released from the Ku protein ring, or else by NEDD8 promoted ubiquitination of Ku protein, causing its release from DNA. # RNF8 in Nucleotide Excision Repair UV-induced formation of pyrimidine dimers in DNA can lead to cell death unless the lesions are repaired. Most repair of these lesions is by nucleotide excision repair. After UV-irradiation, RNF8 is recruited to sites of UV-induced DNA damage and ubiquitinates chromatin component histone H2A. These responses provide partial protection against UV irradiation. # Impaired spermatogenesis Spermatogenesis is the process in which spermatozoa are produced from spermatogonial stem cells by way of mitosis and meiosis. A major function of meiosis is homologous recombinational repair of this germline DNA. RNF8 plays an essential role in signaling the presence of DNA double-strand breaks. Male mice with a gene knockout for RNF8 have impaired spermatogenesis, apparently due to a defect in homologous recombinational repair. # Interactions RNF8 has been shown to interact with Retinoid X receptor alpha.

ROMK The renal outer medullary potassium channel (ROMK) is an ATP-dependent potassium channel (Kir1.1) that transports potassium out of cells. It plays an important role in potassium recycling in the thick ascending limb (TAL) and potassium secretion in the cortical collecting duct (CCD) of the nephron. In humans, ROMK is encoded by the KCNJ1 (potassium inwardly-rectifying channel, subfamily J, member 1) gene.Multiple transcript variants encoding different isoforms have been found for this gene. # Function Potassium channels are present in most mammalian cells, where they participate in a wide range of physiologic responses.The protein encoded by this gene is an integral membrane protein and inward-rectifier type potassium channel.It is inhibited by internal ATP and probably plays an important role in potassium homeostasis.The encoded protein has a greater tendency to allow potassium to flow into a cell rather than out of a cell (hence the term "inwardly rectifying").ROMK was identified as the pore-forming component of the mitochondrial ATP-sensitive potassium (mitoKATP) channel, known to play a critical role in cardioprotection against ischemic-reperfusion injury in the heart as well as in the protection against hypoxia-induced brain injury from stroke or other ischemic attacks. # Clinical significance Mutations in this gene have been associated with antenatal Bartter syndrome, which is characterized by salt wasting, hypokalemic alkalosis, hypercalciuria, and low blood pressure. # Role in hypokalemia and magnesium deficiency The ROMK channels are inhibited by magnesium in the nephron's normal physiologic state.In states of hypokalemia (a state of potassium deficiency), concurrent magnesium deficiency results in a state of hypokalemia that may be more difficult to correct with potassium replacement alone.This may be directly due to decreased inhibition of the outward potassium current in states where magnesium is low.Conversely, magnesium deficiency alone is not likely to cause a state of hypokalemia .

ROR1 Tyrosine-protein kinase transmembrane receptor ROR1, also known as neurotrophic tyrosine kinase, receptor-related 1 (NTRKR1), is an enzyme that in humans is encoded by the ROR1 gene. ROR1 is a member of the receptor tyrosine kinase-like orphan receptor (ROR) family. # Function The protein encoded by this gene is a receptor tyrosine kinase that modulates neurite growth in the central nervous system.It is a type I membrane protein and belongs to the ROR subfamily of cell surface receptors.ROR1 is currently under investigation for its role in the metastasis of cancer cells. ROR1 has recently been shown to be expressed on ovarian cancer stem cell, on which it seems to play a functional role in promoting migration/invasion or spheroid formation in vitro and tumor engraftment in immune-deficient mice.Treatment with a humanized mAb specific for ROR1 (UC-961) could inhibit the capacity of ovarian cancer cells to migrate, form spheroids, or engraft immune-deficient mice.Moreover, such treatment inhibited the growth of tumor xenografts, which in turn had a reduced capacity to engraft immune-deficient mice and were relatively depleted of cells with features of CSC, suggesting that treatment with UC-961 could impair CSC renewal.Collectively, these studies indicate that ovarian CSCs express ROR1, which may be targeted for anti-CSC therapy.

ROR2 Tyrosine-protein kinase transmembrane receptor ROR2 also known as neurotrophic tyrosine kinase, receptor-related 2, is a protein that in humans is encoded by the ROR2 gene located on position 9 of the long arm of chromosome 9.This protein is responsible for aspects of bone and cartilage growth.It is involved in Robinow syndrome and autosomal dominant brachydactyly type B. ROR2 is a member of the receptor tyrosine kinase-like orphan receptor (ROR) family. # Function The protein encoded by this gene is a receptor tyrosine kinase and type I transmembrane protein that belongs to the ROR subfamily of cell surface receptors.The protein may be involved in the early formation of the chondrocytes and may be required for cartilage and growth plate development. # Clinical significance Mutations in this gene can cause brachydactyly type B, a skeletal disorder characterized by hypoplasia/aplasia of distal phalanges and nails.In addition, mutations in this gene can cause the autosomal recessive form of Robinow syndrome, which is characterized by skeletal dysplasia with generalized limb bone shortening, segmental defects of the spine, brachydactyly, and a dysmorphic facial appearance.

ROS1 Proto-oncogene tyrosine-protein kinase ROS is an enzyme that in humans is encoded by the ROS1 gene. # Function This proto-oncogene, highly expressed in a variety of tumor cell lines, belongs to the sevenless subfamily of tyrosine kinase insulin receptor genes.The protein encoded by this gene is a type I integral membrane protein with tyrosine kinase activity.The protein may function as a growth or differentiation factor receptor. # Role in cancer ROS1 is a receptor tyrosine kinase (encoded by the gene ROS1) with structural similarity to the anaplastic lymphoma kinase (ALK) protein; it is encoded by the c-ros oncogene and was first identified in 1986. The exact role of the ROS1 protein in normal development, as well as its normal physiologic ligand, have not been defined.Nonetheless, as gene rearrangement events involving ROS1 have been described in lung and other cancers, and since such tumors have been found to be remarkably responsive to small molecule tyrosine kinase inhibitors, interest in identifying ROS1 rearrangements as a therapeutic target in cancer has been increasing.Recently, the small molecule tyrosine kinase inhibitor, crizotinib, was approved for the treatment of patients with metastatic NSCLC whose tumors are ROS1 -positive. Gene rearrangements involving the ROS1 gene were first detected in glioblastoma tumors and cell lines.In 2007 a ROS1 rearrangement was identified in a cell line derived from a lung adenocarcinoma patient. Since that discovery, multiple studies have demonstrated an incidence of approximately 1% in lung cancers, demonstrated oncogenicity, and showed that inhibition of tumor cells bearing ROS1 gene fusions by crizotinib or other ROS1 tyrosine kinase inhibitors was effective in vitro. Clinical data supports the use of crizotinib in lung cancer patients with ROS1 gene fusions.Preclinical and clinical work suggests multiple potential mechanisms of drug resistance in ROS1 + lung cancer, including kinase domain mutations in ROS1 and bypass signaling via RAS and EGFR. Although the most preclinical and clinical studies of ROS1 gene fusions have been performed in lung cancer, ROS1 fusions have been detected in multiple other tumor histologies, including ovarian carcinoma, sarcoma, cholangiocarcinomas and others.Crizotinib or other ROS1 inhibitors may be effective in other tumor histologies beyond lung cancer as demonstrated by a patient with an inflammatory myofibroblastic tumor harboring a ROS1 fusion with a dramatic response to crizotinib. # Preclinical findings From a large-scale survey of tyrosine kinase activity in non-small cell lung cancer (NSCLC), and identified more than 50 distinct tyrosine kinases and over 2500 downstream substrates, with the goal of identifying candidate oncogenes.In a sampling of 96 tissue samples from NSCLC patients, approximately 30% displayed high levels of phosphotyrosine expression; further analysis was conducted to identify highly phosphorylated tyrosine kinases in NSCLC from a panel of 41 NSCLC cell lines, and 150 patient samples.Among the top 20 receptor tyrosine kinases identified in this analysis, 15 were identified in both cell lines and tumors, and among these were both ALK and These initial findings paved the way for more expansive analyses of ROS1 kinase fusions in NSCLC and other cancers. # Fusion prevalence In patients with NSCLC, approximately 2% are positive for a ROS1 gene rearrangement, and these rearrangements are mutually exclusive of ALK rearrangement. ROS1 fusion-positive patients tend to be younger, with a median age of 49.8 years, and never-smokers, with a diagnosis of adenocarcinoma. There is a higher representation of Asian ethnicity and patients with Stage IV disease.ROS1 rearrangements are estimated to be roughly half as common as ALK-rearranged NSCLCs.Similar to ALK-rearranged, ROS1-rearranged NSCLC have younger age of onset and a non-smoking history.A benefit of a small-molecule ALK, ROS1 , and cMET inhibitor, crizotinib, was also shown in this patient group. ROS1 expression was found in approximately 2% of NSCLC patients, and its expression was limited to those patients with ROS1 gene fusions.Similar findings were reported in a separate analysis of 447 NSCLC samples, of which 1.2% were found to be positive for ROS1 rearrangement; this study also confirmed the activity of the ALK/ROS1 /cMET inhibitor crizotinib in ROS1 -positive tumors.ROS1 fusions were also identified in approximately 2% of adenocarcinomas and 1% of glioblastoma samples in an assessment of kinase fusions across different cancers. Table 1: Sampling of ROS1 Rearrangements Observed in NSCLC and Other Cancers. All of the kinase fusions retain the tyrosine kinase domain of ROS1 . List is not exhaustive. (Adapted from Stumpfova 2012). - Multiple variant isoforms observed CD74; cluster of differentiation 74, long/short isoforms; EZR; ezrin; FIG; fused in glioblastoma; SDC4; LRIG3; leucine-rich repeats and immunoglobulin-like domains 3; SDC; syndecan 4; SLC34A2; solute carrier family 34 (sodium phosphate), member 2; TPM3; tropomyosin 3 # As a drug target Several drugs target ROS1 fusions in cancer, with varying levels of success; most of the drugs to date have been tested only for ROS1-positive non-small cell lung carcinoma (NSCLC).However, some clinical trials (like those for entrectinib, DS-6051b, and TPX-0005) accept patients with ROS1 cancer in any type of solid tumor. - Crizotinib is approved for treating metastatic ROS1-positive NSCLC in many countries.In clinical trials, crizotinib was shown to be effective for 70-80% of ROS1+ NSCLC patients, but it does not effectively treat the brain.Some patients have a response that lasts for years.Crizotinib is available to patients with solid tumors other than NSCLC through clinical trials. - Entrectinib (RXDX-101) is a selective tyrosine kinase inhibitor developed by Ignyta, Inc., with specificity, at low nanomolar concentrations, for all of three Trk proteins (encoded by the three NTRK genes, respectively) as well as the ROS1, and ALK receptor tyrosine kinases. An open label, multicenter, global phase 2 clinical trial called STARTRK-2 started in 2015 to test the drug in patients with ROS1/NTRK/ALK gene rearrangements. - Lorlatinib (also known as PF-06463922) was shown in an ongoing Phase 2 clinical trial to be effective in some ROS1+ NSCLC patients, and treats the cancer in the brain as well as the body.Lorlatinib has the potential to overcome certain resistance mutations that develop during treatment with crizotinib. - Ceritinib demonstrates clinical activity (including treating the brain) in ROS1+ NSCLC patients who had previously received platinum-based chemotherapy.In preclinical studies, ceritinib is unable to overcome most ROS1 resistance mutations, including ROS1 G2032R. It has more severe side effects than crizotinib for some patients.Ceritinib is US FDA approved for first line treatment of ALK+ metastatic non-small cell lung cancer. - TPX-0005 preclinical data suggests it is a potent inhibitor of ROS1+ cancer.A Phase I clinical trial opened in March 2017 for patients with advanced solid tumors harboring ALK, ROS1, or NTRK1-3 rearrangements. - DS-6051b preclinical data show it is active against ROS1-positive cancers.It is an ongoing clinical trial. - Cabozantinib preclinical data has shown the drug might overcome crizotinib resistance in ROS1+ cancer in early studies.However, the required dosage makes the drug difficult to tolerate for many patients.Cabozantinib is US FDA approved for metastatic medullary thyroid cancer (as Cometriq) and renal cell carcinoma (as Cabometyx). # Global ROS1 Initiative The Global ROS1 Initiative is a worldwide, multi-stakeholder collaboration with a goal of improving patient outcomes and accelerating research for any type of ROS1+ cancer.It is the first such collaboration focused on cancers driven by a single oncogene and was initiated by ROS1+ cancer patients and carers who call themselves "The ROS1ders.";their website tracks targeted therapies, clinical trials, world experts and new developments for ROS1+ cancers.Partners in the Initiative include patient-focused nonprofits Bonnie J. Addario Lung Cancer Foundation and Addario Lung Cancer Medical Institute, clinicians who treat ROS1+ patients, ROS1 researchers, pharmaceutical firms and biotech companies.

RPN2 Dolichyl-diphosphooligosaccharide—protein glycosyltransferase subunit 2, also called ribophorin ǁ is an enzyme that in humans is encoded by the RPN2 gene. # Function This gene encodes a type I integral ribophorin membrane protein found only in the rough endoplasmic reticulum.The encoded protein is part of an N-oligosaccharyl transferase complex that links high mannose oligosaccharides to asparagine residues found in the Asn-X-Ser/Thr consensus motif of nascent polypeptide chains.This protein is similar in sequence to the yeast oligosaccharyl transferase subunit SWP1.RPN2 has been demonstrated to be a prognostic marker of human cancer, and may be a potential target of clinical importance. # Structure ## Gene The RPN2 gene lies on the chromosome location of 20q11.23 and consists of 19 exons. ## Protein RPN2 consists of 631 amino acid residues and weighs 69284Da. # Function RPN2 is a unique integral glycoprotein in rough ER membrane that is involved in translocation and the maintenance of the structural uniqueness of the rough ER.It is also an essential subunit of N-oligosaccharyl transferase complex that conjugates high mannose oligosaccharides to asparagine residues in the N-X-S/T consensus motif of nascent polypeptide chains.RPN2 regulates the glycosylation of multi-drug resistance, and thus its interference could decrease the membrane localization of P-glycoprotein by reducing its glycosylation status and restored the sensitivity to docetaxel. # Clinical significance RPN2 has been demonstrated to be a prognostic marker of human cancer.RPN2 is highly expressed in breast cancer stem cells and is associated with tumor metastasis.Recent study has shown that its expression is correlated with clinically aggressive features of breast cancer, implying a possible application in personalized medicine.RPN2 silencing has been reported to repress tumorigenicity and to sensitize the tumors to cisplatin treatment, which led to the longer survival of NSCLC-bearing mice, suggesting that RPN2 may represent a promising new target for RNAi-based medicine against NSCLC.Similar potential application has also been shown in osteosarcoma, esophageal squamous cell carcinoma and colorectal cancer.RPN2 is also reported to be one of the prothrombin-binding proteins on monocyte surfaces, suggesting that its involvement in the pathophysiology of thrombosis in patients with APS. # Interactions P53 tetraspanin CD63 prothrombin # Model organisms Model organisms have been used in the study of RPN2 function.A conditional knockout mouse line, called Rpn2tm1a(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 six 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.

RRM1 Ribonucleoside-diphosphate reductase large subunit is an enzyme that in humans is encoded by the RRM1 gene. This gene encodes one of two non-identical subunits which constitute ribonucleoside-diphosphate reductase, an enzyme essential for the production of deoxyribonucleotides prior to DNA synthesis in S phase of dividing cells.It is one of several genes located in the imprinted gene domain of 11p15.5, an important tumor-suppressor gene region.Alterations in this region have been associated with the Beckwith-Wiedemann syndrome, Wilms tumor, rhabdomyosarcoma, adrenocortical carcinoma, and lung, ovarian, and breast cancer.This gene may play a role in malignancies and disease that involve this region.This gene is oriented in a head-to-tail configuration with the stromal interaction molecule 1 gene (STIM1), with the 3' end of STIM1 situated 1.6 kb from the 5' end of this gene. # Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles. - ↑ The interactive pathway map can be edited at WikiPathways: "FluoropyrimidineActivity_WP1601"..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}

RRM2 Ribonucleoside-diphosphate reductase subunit M2, also known as ribonucleotide reductase small subunit, is an enzyme that in humans is encoded by the RRM2 gene. # Function This gene encodes one of two non-identical subunits for ribonucleotide reductase.This reductase catalyzes the formation of deoxyribonucleotides from ribonucleotides.Synthesis of the encoded protein (M2) is regulated in a cell-cycle dependent fashion.Transcription from this gene can initiate from alternative promoters, which results in two isoforms that differ in the lengths of their N-termini. # Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles. - ↑ The interactive pathway map can be edited at WikiPathways: "FluoropyrimidineActivity_WP1601"..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}

RSU1 Ras suppressor protein 1 is a protein that in humans is encoded by the RSU1 gene. This gene encodes a protein that is involved in the Ras signal transduction pathway, growth inhibition, and nerve-growth factor induced differentiation processes, as determined in mouse and human cell line studies.In mouse, the encoded protein was initially isolated based on its ability to inhibit v-Ras transformation.Multiple alternatively spliced transcript variants for this gene have been reported; one of these variants was found only in glioma tumors. RSU-1 has also been seen to act as a structural protein in integrin-mediated focal-adhesion complexes.It bind strongly to the protein PINCH.

RTF1 Rtf1, Paf1/RNA polymerase II complex component, homolog (S. cerevisiae) is a protein that in humans is encoded by the RTF1 gene. This locus may represent a gene involved in regulation of transcription elongation and chromatin remodeling, based on studies of similar proteins in other organisms.The encoded protein may bind single-stranded DNA. # Model organisms Model organisms have been used in the study of RTF1 function.A conditional knockout mouse line, called Rtf1tm1a(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. 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 three 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; vertebral fusion was observed in male animals.

RTL6 Retrotransposon Gag Like 6 is a protein encoded by the RTL6 gene in humans.RTL6 is a member of the Mart family of genes, which are related to Sushi-like retrotransposons and were derived from fish and amphibians.The RTL6 protein is localized to the nucleus and has a predicted leucine zipper motif that is known to bind nucleic acids in similar proteins, such as LDOC1. # Gene ## Locus The gene is on Chromosome 22 (human) at 22q13.31 on the minus strand from 44492570-44498125 nt on the GRCh38.p7 assembly of the human genome.Aliases for the gene include LDOC1L, MAR6, MART6, and SIRH3.RTL6 is made up of 2 exons and is encoded by 5556 base pairs of DNA . ## Origin RTL6 is a retrotransposon GAG related gene.It is one of eleven MART (Mammalian Retrotransposon Derived) genes in humans related to Sushi-like retrotransposons with long terminal repeats from fish and amphibians.Between 170-310 MYA, MART genes lost their ability to retrotranspose and concomitantly gained new, beneficial function for its host organism. # mRNA RTL6 has an alternate start of transcription 140 base pairs upstream of the normal transcribed region.The lengths of the primary mRNA and that with the upstream start of transcription are 5355 and 5495 base pairs respectively. # Protein ## Primary Information The primary amino acid sequence for RTL6 is made up of 239 residues.There are no known alternative splice variants of the protein.The molecular weight of the protein is 26.2 kDa and the isoelectric point is 11.58.RTL6 is a proline and arginine rich protein. ## Domains and Motifs RTL6 contains a predicted leucine zipper motif known to participate in nucleic acid binding in other proteins. RTL6 also contains a domain of unknown function from amino acid residues 98-177 .RTL6 is one of a number of genes belonging to the DUF4939 (domain of unknown function) superfamily. ## Secondary structure The secondary structure of RTL6 is made up of largely alpha helices.One region of RTL6 is also predicted to participate in a coiled-coil structure from amino acid residues 29-63. ## Post-translational modifications There are also two predicted phosphorylation sites for Protein Kinase C with high confidence scores at amino acid residues 6 and 45.There is also a predicted ubiquitination site with medium-confidence at amino acid residue 8. ## Cellular sublocation RTL6 is expected to be localized to the nucleus and cytosol based on the presence of a leucine zipper domain, the absence of signals indicating secretion or transmembrane domains, and immunohistochemical staining. # Expression RTL6 has been shown to be expressed at high levels during all stages of development and in a wide variety of tissues. RTL6 expression has been shown to fall in HeLa cervical cancer cells upon treatment with chemotherapeutic Casiopeinas and in A549 lung cancer cells upon treatment with Actinomycin D. # Interacting proteins RTL6 has been shown to interact with the following proteins: # Clinical Significance The RTL6 protein has been shown to interact with the UXAC protein from Yersinia pestis, the gram-negative bacterium responsible for the bubonic plague. # Homology/evolution ## Paralogs Eleven paralogs were identified for RTL6 in humans.The paralogs have diverse functions and expression patterns, although many are known to have zinc finger domains and bind nucleic acids: ## Orthologs RTL6 is highly conserved across mammals, including the leucine zipper motif and DUF4939. The gene is also conserved in marsupials such as the opossum but not in birds such as the chicken, suggesting the gene was likely formed after the divergence of mammals and birds but before the divergence of marsupials and mammals (170-310 MYA: The most distantly detectable organisms with homology in the gene are bony fishes including salmon and the common carp, but similarity to the human protein sequence is markedly less than that of mammals.No traces of the gene can be seen in intermediates between mammals and bony fishes such as reptiles or amphibians:

RTN1 Reticulon-1 also known as neuroendocrine-specific protein (NSP) is a protein that in humans is encoded by the RTN1 gene. This gene belongs to the family of reticulon-encoding genes.Reticulons are associated with the endoplasmic reticulum, and are involved in neuroendocrine secretion or in membrane trafficking in neuroendocrine cells.Alternatively spliced transcript variants encoding different isoforms have been identified.Multiple promoters rather than alternative splicing of internal exons seem to be involved in this diversity. # Interactions RTN1 has been shown to interact with BCL2-like 1 and UGCG.

RYR1 Ryanodine receptor 1 (RYR-1) also known as skeletal muscle calcium release channel or skeletal muscle-type ryanodine receptor is a protein found primarily in skeletal muscle.In humans, it is encoded by the RYR1 gene. # Function RYR1 functions as a calcium release channel in the sarcoplasmic reticulum, as well as a connection between the sarcoplasmic reticulum and the transverse tubule.RYR1 is associated with the dihydropyridine receptor (L-type calcium channels) within the sarcolemma of the T-tubule, which opens in response to depolarization, and thus effectively means that the RYR1 channel opens in response to depolarization of the cell. RYR1 plays a signaling role during embryonic skeletal myogenesis.A correlation exists between RYR1-mediated Ca2+ signaling and the expression of multiple molecules involved in key myogenic signaling pathways.Of these, more than 10 differentially expressed genes belong to the Wnt family which are essential for differentiation.This coincides with the observation that without RYR1 present, muscle cells appear in smaller groups, are underdeveloped, and lack organization.Fiber type composition is also affected, with less type 1 muscle fibers when there are decreased amounts of RYR1.These findings demonstrate RYR1 has a non-contractile role during muscle development. RYR1 is mechanically linked to neuromuscular junctions for the calcium release-calcium induced biological process.While nerve-derived signals are required for acetylcholine receptor cluster distribution, there is evidence to suggest RYR1 activity is an important mediator in the formation and patterning of these receptors during embryological development.The signals from the nerve and RYR1 activity appear to counterbalance each other.When RYR1 is eliminated, the acetylcholine receptor clusters appear in an abnormally narrow pattern, yet without signals from the nerve, the clusters are scattered and broad.Although their direct role is still unknown, RYR1 is required for proper distribution of acetylcholine receptor clusters. # Clinical significance Mutations in the RYR1 gene are associated with malignant hyperthermia susceptibility, central core disease, minicore myopathy with external ophthalmoplegia and samaritan myopathy, a benign congenital myopathy.Alternatively spliced transcripts encoding different isoforms have been demonstrated.Dantrolene may be the only known drug that is effective during cases of malignant hyperthermia. # Interactions RYR1 has been shown to interact with: - calmodulin - FKBP1A - HOMER1 - HOMER2 - HOMER3 and - TRDN.

Rap1 Rap1 (Ras-proximate-1 or Ras-related protein 1) is a small GTPase, which are small cytosolic proteins that act like cellular switches and are vital for effective signal transduction.There are two isoforms of the Rap1 protein, each encoded by a separate gene, RAP1A and RAP1B. Rap1 belongs to Ras-related protein family. GTPases are inactive when in their GDP-bound form, and become active when they bind to GTP. GTPase activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs) regulate small GTPases, with GAPs promoting the GDP-bound (inactive) form, and GEFs promoting the GTP-bound (active) form. When bound to GTP, small GTPases regulate myriad cellular processes. These proteins are divided into families depending on their protein structure, and the most well studied is the Ras superfamily, of which Rap1 is a member.Whereas Ras is known for its role in cell proliferation and survival, Rap1 is predominantly involved in cell adhesion and cell junction formation.Ras and Rap are regulated by different sets of guanine nucleotide exchange factors and GTPase-activating proteins, thus providing one level of specificity. # Effectors ## RAPL The identification of Rap1 effector proteins has provided important insights into mechanisms by which Rap1 regulates T-cell receptor (TCR) signaling to integrins.A constitutively active Rap1 construct, Rap1G12V, was used as a bait in a yeast two-hybrid screen to identify RAPL as a Rap1-binding protein. Overexpression of RAPL enhances LFA-1 clustering and adhesion, and RAPL-deficient lymphocytes and dendritic cells exhibit impaired adhesion and migration.RAPL is also an integrin-associated protein as RAPL polarizes to the immunological synapse following antigen stimulation of T cells, colocalizes with LFA-1 following TCR or chemokine stimulation, and co-immunoprecipitates with LFA-1 in a Rap1-dependent manner (108).This interaction between RAPL and LFA-1 is dependent on lysine residues at positions 1097 and 1099 in the juxtamembrane region of the αL-subunit cytoplasmic domain.This is a functionally significant region of the αL cytoplasmic domain as deletion of the adjacent GFFKR motif results in a constitutively active LFA-1 integrin (124, 125).While lysines 1097 and 1099 are critical for Rap1-dependent activation of LFA-1, the β2-subunit cytoplasmic domain appears to be dispensable for activation of LFA-1 by Rap1 (126).Mutation of these lysine residues to alanine impairs the ability of LFA-1 to redistribute to the leading edge induced by Rap1 activation or overexpression of RAPL.Because RAPL localizes to the leading edge properly in cells expressing this mutant LFA-1, this finding suggests that RAPL may play a critical role in localizing LFA-1 to discrete regions of the plasma membrane. ## Mst1 The serine–threonine kinase Mst1, a member of a family of kinases homologous to the Ste20 kinase in yeast, has recently been identified as a RAPL effector.TCR-mediated activation of Mst1 is dependent on RAPL, and TCR-mediated adhesion to ICAM-1 and antigen-dependent conjugate formation are impaired following RNAi-mediated knockdown of Mst1 expression.Although Rap1 and RAPL have been shown to regulate both LFA-1 affinity and clustering, overexpression of Mst1 only enhances LFA-1 clustering.This finding suggests that LFA-1 clustering is critical for TCR signaling to integrins that is mediated by Rap1.It also implies the existence of Mst1-independent mechanisms by which Rap1 regulates LFA-1 affinity. ## PKD A striking feature of Rap1 and the Rap1-associated signaling proteins PKD, RAPL, and Mst1 is their localization to membranes where integrins are found.This provides a mechanism by which Rap1 can act directly on integrins and modulate integrin affinity and/or clustering.PKD, RAPL, and Mst1 have also all been proposed to play a role in movement of receptors to the plasma membrane.PKD-dependent regulation of vesicular transport requires PKD kinase activity, while PKD-dependent regulation of TCR signaling to integrins does not appear to require PKD kinase activity.Thus, PKD may play a distinct role in regulating Rap1-dependent integrin regulation.For example, the PKD-dependent association of Rap1 with C3G suggests that PKD may be critical for localizing Rap1 not only with integrins but also with Rap1 GEFs.The PKD–Rap1 interaction may thus be central to the subsequent activation of Rap1 and triggering of downstream effectors such as RAPL and Mst1. ## RIAM An additional Rap1 effector provides a link between Rap1 and the actin cytoskeleton.RIAM (Rap1–GTP-interacting adapter molecule) is a broadly expressed adaptor protein that contains an RA (Ras association)-like domain, a PH domain, and several proline-rich sequences.Like RAPL, RIAM interacts preferentially with active Rap1, and overexpression of RIAM enhances integrin-mediated adhesion.In addition, knockdown of RIAM inhibits adhesion induced by active Rap1 and inhibits the localization of active Rap1 at the plasma membrane.The ability of RIAM to associate with profilin, Ena/VASP proteins, and talin suggests that RIAM promotes Rap1-dependent integrin activation through effects on the actin cytoskeleton, particularly the interaction of talin with integrin cytoplasmic tails.Given the known role of talin in regulating integrin affinity, RIAM may provide an Mst1-independent mechanism by which Rap1 regulates integrin affinity.

Rex1 Rex1 (Zfp-42) is a known marker of pluripotency, and is usually found in undifferentiated embryonic stem cells.In addition to being a marker for pluripotency, its regulation is also critical in maintaining a pluripotent state.As the cells begin to differentiate, Rex1 is severely and abruptly downregulated. # Discovery Rex1 was discovered by Hosler, BA et al.in 1989 when studying F9 murine teratocarcinoma stem cells.They found that these teratocarcinoma stem cells expressed high levels of Rex1, and that they resembled pluripotent stem cells of the inner cell mass (ICM).Hosler, BA et al.found that these teratocarcinoma stem cells, when in the presence of retinoic acid (RA), differentiated into nontumorigenic cells resembling extraembryonic endoderm of early mouse embryos.They were able to isolate the nucleotide sequence for Rex1 using differential hybridization of an F9 cell.They named it Rex1 for reduced expression 1 because there was a steady decline of its mRNA levels within 12 hours of the addition of RA. # Structure Rex1 is a protein that in humans is encoded by the ZFP42 gene.The Rex1 protein is 310 amino acids long, and has four closely spaced zinc fingers at 188-212, 217-239, 245-269, and 275-299. # p38 MAPK & Mesenchymal Stem Cells Rex1 has been found to be critically important in maintaining proliferative state in mesenchymal stem cells (MSC), while simultaneously preventing differentiation.Both umbilical cord blood MSC and adipose MSC express high levels of Rex1, while bone marrow MSC expressed low levels of Rex1.Proliferation rates are highly correlated with Rex1 expression levels, meaning high Rex1 expression is correlated with high levels of proliferation.The MSCs with weak Rex1 expression, have activated p38 MAPK and high expression levels of MKK3.Thus, Rex1 expression is inversely correlated with p38 MAPK activation, and positively correlated with high proliferation rates.Rex1 was found to inhibit MKK3 expression, which activates p38 MAPK.Activated p38 MAPK, in turn, inhibits proliferation.Rex1 was also found to inhibit NOTCH and STAT3, two transcription factors which lead to differentiation.Therefore, Rex1 expression allows for high levels of proliferation, and prevents differentiation through a network of various transcription factors and protein kinases. # Embryo Development ## Tissue Derivation During embryogenesis, the inner cell mass (ICM) is separated from the trophoblast.The stem cells derived from the ICM and trophectoderm have been found to express high levels of Oct3/4 and Rex1.As the ICM matures and begins to form the epiblast, and primitive ectoderm, the cells in the ICM have been found to be a heterogenous population, with varying levels of Rex1 expression.Rex1−/Oct3/4− triggers trophectoderm differentiation, while Rex1+/Oct3/4+ cells predominantly differentiate into primitive endoderm and mesoderm.Also, Rex1−/Oct3/4+ cells differentiate into cells of primitive ectoderm, the somatic cell lineage. ## Gene Control Studies have shown that PEG3 and Nespas are downstream targets of Rex1.Rex1 can control the expression of Peg3 via epigenetic changes.YY1 has been shown to be involved in setting up DNA methylation on the maternal allele of PEG3 during oogenesis.Rex1 was found to protect the paternal allele from being methylated, and keep the PEG3 gene unmethylated during early embryogenesis.Rex1 exhibits gene control in developing embryos via its epigenetic control on genes such as PEG3, which has been identified as playing a key role in fetal growth rates # Expression in Adult Tissues The only adult tissue Rex1 has been identified in are the testicles.Using in situ hybridization it was determined that the spermatocytes in the more inner layers of the testicles are expressing Rex1.Thus, the male germ cells undergoing meiosis are the specific cells in the testicles that express Rex1.It has not been observed, however, that Rex1 is expressed in the female germ cells. # Rex1 Interactions with Other Transcription Factors Rex1 participates in a network of transcription factors that all work to regulate each other via varying expression levels. ## Nanog The Nanog protein has been found to be a transcriptional activator for the Rex-1 promoter, playing a key role in sustaining Rex1 expression.Knockdown of Nanog in embryonic stem cells results in a reduction of Rex-1 expression, while forced expression of Nanog stimulates Rex-1 expression.Nanog regulates the transcription of Rex1 through 2 strong transactivation domains on the C-terminus which are required to activate the Rex1 promoter. ## NOTCH Rex1 has been found to inhibit the expression of NOTCH, thus preventing differentiation. ## STAT3 Rex1 has been found to inhibit the expression of STAT3, thus preventing differentiation. ## Sox2 Cooperative regulation of Rex1 is seen with Sox2 and Nanog. ## Oct3/4 Oct3/4 can both repress and activate the Rex1 promoter.In cells that already express high level of Oct3/4, exogenously transfected Oct3/4 will lead to the repression of Rex1.However, in cells that are not actively expressing Oct3/4, an exogenous transfection of Oct3/4 will lead to the activation of Rex1.This implies a dual regulatory ability of Oct3/4 on Rex1.At low levels of the Oct3/4 protein, the Rex1 promoter is activated, while at high levels of the Oct3/4 protein, the Rex1 promoter is repressed.

SBDS Ribosome maturation protein SBDS is a protein that in humans is encoded by the SBDS gene.An alternative transcript has been described, but its biological nature has not been determined.This gene has a closely linked pseudogene that is distally located.This gene encodes a member of a highly conserved protein family that exists from archaea to vertebrates and plants. # Function The encoded protein may function in RNA metabolism.The precise function of the SBDS protein is not known but it appears to play an important role in ribosome function or assembly.Knockdown of SBDS expression results in increased apoptosis in erythroid cells undergoing differentiation due to elevated ROS levels.Hence SBDS is critical for normal erythropoiesis. This family is highly conserved in species ranging from archaea to vertebrates and plants.The family contains several Shwachman-Bodian-Diamond syndrome (SBDS) proteins from both mouse and humans.Shwachman-Diamond syndrome is an autosomal recessive disorder with clinical features that include pancreatic exocrine insufficiency, haematological dysfunction and skeletal abnormalities.Members of this family play a role in RNA metabolism. A number of uncharacterised hydrophilic proteins of about 30 kDa share regions of similarity.These include, - Mouse protein 22A3. - Saccharomyces cerevisiae chromosome XII hypothetical protein YLR022c. - Caenorhabditis elegans hypothetical protein W06E11.4. - Methanococcus jannaschii hypothetical protein MJ0592. This particular protein sequence is highly conserved in species ranging from archaea to vertebrates and plants. # Structure The SBDS protein contains three domains, an N-terminal conserved FYSH domain, central helical domain and C-terminal domain containing an RNA-binding motif. # SBDS N-terminal domain ## Function This protein domain appears to be very important, since mutations in this domain are usually the cause of Shwachman-Bodian-Diamond syndrome.It shares distant structural and sequence homology to a protein named YHR087W found in the yeast Saccharomyces cerevisiae.The protein YHR087W is involved in RNA metabolism, so it is probable that the SBDS N-terminal domain has the same function. ## Structure The N-terminal domains contains a novel mixed alphabeta fold, four beta-strands, and four alpha-helices arranged as a three beta stranded anti-parallel-sheet. # SBDS central domain ## Function The function of this protein domain has been difficult to elucidate.It is possible that it has a role in binding to DNA or RNA.Protein binding to form a protein complex is also another possibility.It has been difficult to infer the function from the structure since this particular domain structure is found in archea. ## Structure This domain contains a very common structure, the winged helix-turn-helix. # SBDS C-terminal domain In molecular biology, the SBDS C-terminal protein domain is highly conserved in species ranging from archaea to vertebrates and plants. ## Function Members of this family are thought to play a role in RNA metabolism.However, its precise function remains to be elucidated.Furthermore, its structure makes it very difficult to predict the protein domain's function. ## Structure The structure of the C-terminal domain contains a ferredoxin-like fold This structure has a four-stranded beta-sheet with two helices on one side. # Clinical significance Mutations within this gene are associated with Shwachman-Bodian-Diamond syndrome .The two most common mutations associated with this syndrome are at positions 183–184 (TA→CT) resulting in a premature stop-codon (K62X) and a frameshift mutation at position 258 (2T→C) resulting in a stopcodon (C84fsX3).

SCO1 Protein SCO1 homolog, mitochondrial, also known as SCO1, cytochrome c oxidase assembly protein, is a protein that in humans is encoded by the SCO1 gene.SCO1 localizes predominantly to blood vessels, whereas SCO2 is barely detectable, as well as to tissues with high levels of oxidative phosphorylation.Expression of SCO2 is also much higher than that of SCO1 in muscle tissue, while SCO1 is expressed at higher levels in liver tissue than SCO2.Mutations in both SCO1 and SCO2 are associated with distinct clinical phenotypes as well as tissue-specific cytochrome c oxidase (complex IV) deficiency. # Structure SCO1 is located on the p arm of chromosome 17 in position 13.1 and has 6 exons.The SCO1 gene produces a 33.8 kDa protein composed of 301 amino acids.The protein is a member of the SCO1/2 family.It contains 3 copper metal binding sites at positions 169, 173, and 260, a transit peptide, a 25 amino acid topological domain from positions 68-92, a 19 amino acid helical transmembrane domain from positions 93-111, and a 190 amino acid topological domain from positions 112-301 in the mitochondrial intermembrane.Additionally, SCO1 has been predicted to contain 10 beta strands, 7 helixes, and 2 turns and is a single-pass membrane protein. # Function Mammalian cytochrome c oxidase (COX) catalyzes the transfer of reducing equivalents from cytochrome c to molecular oxygen and pumps protons across the inner mitochondrial membrane.In yeast, 2 related COX assembly genes, SCO1 and SCO2 (synthesis of cytochrome c oxidase), enable subunits 1 and 2 to be incorporated into the holoprotein.This gene is the human homolog to the yeast SCO1 gene.It is predominantly expressed in muscle, heart, and brain tissues, which are also known for their high rates of oxidative phosphorylation.SCO1 is a copper metallochaperone that is located in the inner mitochondrial membrane and is important for the maturation and stabilization of cytochrome c oxidase subunit II (MT-CO2/COX2).It plays a role in the regulation of copper homeostasis by controlling the localization and abundance of CTR1 and is responsible for the transportation of copper to the Cu(A) site on MT-CO2/COX2. # Clinical relevance Mutations in the SCO1 gene are associated with hepatic failure and encephalopathy resulting from mitochondrial complex IV deficiency also known as cytochrome c oxidase deficiency.This is a disorder of the mitochondrial respiratory chain with heterogeneous clinical manifestations, ranging from isolated myopathy to severe multisystem disease affecting several tissues and organs.Features include hypertrophic cardiomyopathy, hepatomegaly and liver dysfunction, hypotonia, muscle weakness, exercise intolerance, developmental delay, delayed motor development, mental retardation, and lactic acidosis.Some affected individuals manifest a fatal hypertrophic cardiomyopathy resulting in neonatal death.A subset of patients also suffer from Leigh syndrome.Specifically, cases of pathogenic SCO1 mutations have resulted in fatal infantile encephalopathy, neonatal-onset hepatic failure, and severe hepatopathy.The P174L and M294V mutations have been identified and implicated in these diseases and phenotypes.It has also been suggested that mutations in SCO1, as well as SCO2, can result in a cellular copper deficiency, which can occur separately from cytochrome c oxidase assembly defects. # Model organisms Model organisms have been used in the study of SCO1 function.A conditional knockout mouse line, called Sco1tm1a(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. 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 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. # Interactions SCO1 has been shown to have 127 binary protein-protein interactions including 120 co-complex interactions.SCO1 interacts with COA6, TMEM177, COX20, COX16, COX17, WDR19, CIDEB, and UBC7.It is also found in a complex with TMEM177, COX20, COA6, MT-CO2/COX2, COX18 and SCO2.

SCP2 Non-specific lipid-transfer protein also known as sterol carrier protein 2 (SCP-2) or propanoyl-CoA C-acyltransferase is a protein that in humans is encoded by the SCP2 gene. # Function This gene encodes two proteins: sterol carrier protein X (SCPx) and sterol carrier protein 2 (SCP2), as a result of transcription initiation from 2 independently regulated promoters.The transcript initiated from the proximal promoter encodes the longer SCPx protein, and the transcript initiated from the distal promoter encodes the shorter SCP2 protein, with the 2 proteins sharing a common C-terminus.Evidence suggests that the SCPx protein is a peroxisome-associated thiolase that is involved in the oxidation of branched chain fatty acids, while the SCP2 protein is thought to be an intracellular lipid transfer protein. Alternative splicing of this gene produces multiple transcript variants, some encoding different isoforms.The full-length nature of all transcript variants has not been determined. # Clinical significance This gene is highly expressed in organs involved in lipid metabolism, and may play a role in Zellweger syndrome, in which cells are deficient in peroxisomes and have impaired bile acid synthesis. # Interactions SCP2 has been shown to interact with Caveolin 1 and peroxisomal receptor PEX5.

SDHA Succinate dehydrogenase complex, subunit A, flavoprotein variant is a protein that in humans is encoded by the SDHA gene.This gene encodes a major catalytic subunit of succinate-ubiquinone oxidoreductase, a complex of the mitochondrial respiratory chain.The complex is composed of four nuclear-encoded subunits and is localized in the mitochondrial inner membrane.SDHA contains the FAD binding site where succinate is deprotonated and converted to fumarate.Mutations in this gene have been associated with a form of mitochondrial respiratory chain deficiency known as Leigh Syndrome.A pseudogene has been identified on chromosome 3q29.Alternatively spliced transcript variants encoding different isoforms have been found for this gene. # Structure The SDHA gene is located on the p arm of chromosome 5 at locus 15 and is composed of 16 exons.The SDHA protein encoded by this gene is 664 amino acids long and weighs 72.7 kDA. # Function The SDH complex is located on the inner membrane of the mitochondria and participates in both the citric acid cycle and the respiratory chain.The succinate dehydrogenase (SDH) protein complex catalyzes the oxidation of succinate (succinate + ubiquinone => fumarate + ubiquinol).Electrons removed from succinate transfer to SDHA, transfer across SDHB through iron sulphur clusters to the SDHC/SDHD subunits on the hydrophobic end of the complex anchored in the mitochondrial membrane. Initially, SDHA oxidizes succinate via deprotonation at the FAD binding site, forming FADH2 and 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 Q pool 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 SDHC.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. SDHA acts as an intermediate in the basic SDH enzyme action: - SDHA converts succinate to fumarate as part of the Citric Acid Cycle.This reaction also converts FAD to FADH2. - Electrons from the FADH2 are transferred to the SDHB subunit iron clusters ,,.This function is part of the Respiratory chain - Finally the electrons are transferred to the Ubiquinone (Q) pool via the SDHC/SDHD subunits. # Clinical significance Bi-allelic mutations (i.e. both copies of the gene are mutated) have been described in Leigh syndrome, a progressive brain disorder that typically appears in infancy or early childhood.Affected children may experience vomiting, seizures, delayed development, muscle weakness, and problems with movement.Heart disease, kidney problems, and difficulty breathing can also occur in people with this disorder.The SDHA gene mutations responsible for Leigh syndrome change single amino acids in the SDHA protein, such as a G555E mutation observed in multiple patients, or result in an abnormally short protein.These genetic changes disrupt the activity of the SDH enzyme, impairing the ability of mitochondria to produce energy.It is not known, however, how mutations in the SDHA gene are related to the specific features of Leigh syndrome. SDHA is a tumour suppressor gene, and heterozygous carriers have an increased risk of paragangliomas as well as pheochromocytomas and renal cancer.Risk management for heterozygous carriers of an SDHA mutation can involve annual urine tests for metanephrines and 3-methoxytyramine and MRIs. # 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}

SDHB Succinate dehydrogenase iron-sulfur subunit, mitochondrial (SDHB) also known as iron-sulfur subunit of complex II (Ip) is a protein that in humans is encoded by the SDHB gene. The succinate dehydrogenase (also called SDH or Complex II) protein complex catalyzes the oxidation of succinate (succinate + ubiquinone => fumarate + ubiquinol).SDHB is one of four protein subunits forming succinate dehydrogenase, the other three being SDHA, SDHC and SDHD.The SDHB subunit is connected to the SDHA subunit on the hydrophilic, catalytic end of the SDH complex.It is also connected to the SDHC/SDHD subunits on the hydrophobic end of the complex anchored in the mitochondrial membrane.The subunit is an iron-sulfur protein with three iron-sulfur clusters.It weighs 30 kDa. # Structure The gene that codes for the SDHB protein is nuclear, not mitochondrial DNA.However, the expressed protein is located in the inner membrane of the mitochondria.The location of the gene in humans is on the first chromosome at locus p36.1-p35.The gene is coded in 1,162 base pairs, partitioned in 8 exons.The expressed protein weighs 31.6 kDa and is composed of 280 amino acids.SDHB contains the iron-sulphur clusters necessary for tunneling electrons through the complex.It is located between SDHA and the two transmembrane subunits SDHC and SDHD. # Function The SDH complex is located on the inner membrane of the mitochondria and participates in both the Citric Acid Cycle and Respiratory chain.SDHB acts as an intermediate in the basic SDH enzyme action shown in Figure 1: - SDHA converts succinate to fumarate as part of the Citric Acid Cycle.This reaction also converts FAD to FADH2. - Electrons from the FADH2 are transferred to the SDHB subunit iron clusters ,,. - Finally the electrons are transferred to the Ubiquinone (Q) pool via the SDHC/SDHD subunits.This function is part of the Respiratory chain. Initially, SDHA oxidizes succinate via deprotonation at the FAD binding site, forming FADH2 and leaving fumarate, loosely bound to the active site, free to exit the protein.Electrons from FADH2 are transferred to the SDHB subunit iron clusters ,, and tunnel along the relay until they reach the iron sulfur cluster.The electrons are then transferred to an awaiting ubiquinone molecule at the Q pool 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 SDHC.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 Germline mutations in the gene can cause familial paraganglioma (in old nomenclature, Paraganglioma Type PGL4).The same condition is often called familial pheochromocytoma.Less frequently, renal cell carcinoma can be caused by this mutation. Paragangliomas related to SDHB mutations have a high rate of malignancy.When malignant, treatment is currently the same as for any malignant paraganglioma/pheochromocytoma. ## Cancer Paragangliomas caused by SDHB mutations have several distinguishing characteristics: - Malignancy is common, ranging from 38%-83% in carriers with disease.In contrast, tumors caused by SDHD mutations are almost always benign.Sporadic paragangliomas are malignant in less than 10% of cases. - Malignant paragangliomas caused by SDHB are usually (perhaps 92%) extra-adrenal.Sporadic pheochromocytomas/paragangliomas are extra-adrenal in less than 10% of cases. - The penetrance of the gene is often reported as 77% by age 50 (i.e. 77% of carriers will have at least one tumour by the age of 50).This is likely an overestimate.Currently (2011), families with silent SDHB mutations are being screened to determine the frequency of silent carriers. - The average age of onset is approximately the same for SDHB vs non-SDHB related disease (approximately 36 years). Mutations causing disease have been seen in exons 1 through 7, but not 8.As with the SDHC and SDHD genes, SDHB is a tumor suppressor gene. Tumor formation generally follows the Knudson "two hit" hypothesis.The first copy of the gene is mutated in all cells, however the second copy functions normally.When the second copy mutates in a certain cell due to a random event, Loss of Heterozygosity (LOH) occurs and the SDHB protein is no longer produced.Tumor formation then becomes possible. Given the fundamental nature of the SDH protein in all cellular function, it is not currently understood why only paraganglionic cells are affected.However, the sensitivity of these cells to oxygen levels may play a role. ## Disease pathways The precise pathway leading from SDHB mutation to tumorigenesis is not determined; there are several proposed mechanisms. ### Generation of reactive oxygen species When succinate-ubiquinone activity is inhibited, electrons that would normally transfer through the SDHB subunit to the Ubiquinone pool are instead transferred to O2 to create Reactive Oxygen Species (ROS) such as superoxide.The dashed red arrow in Figure 2 shows this.ROS accumulate and stabilize the production of HIF1-α.HIF1-α combines with HIF1-β to form the stable HIF heterodimeric complex, in turn leading to the induction of antiapoptotic genes in the cell nucleus. ### Succinate accumulation in the cytosol SDH inactivation can block the oxidation of succinate, starting a cascade of reactions: - The succinate accumulated in the mitochondrial matrix diffuses through the inner and outer mitochondrial membranes to the cytosol (purple dashed arrows in Figure 2). - Under normal cellular function, HIF1-α in the cytosol is quickly hydroxylated by prolyl hydroxylase (PHD), shown with the light blue arrow.This process is blocked by the accumulated succinate. - HIF1-α stabilizes and passes to the cell nucleus (orange arrow) where it combines with HIF1-β to form an active HIF complex that induces the expression of tumor causing genes. This pathway raises the possibility of a therapeutic treatment.The build-up of succinate inhibits PHD activity.PHD action normally requires oxygen and alpha-ketoglutarate as cosubstrates and ferrous iron and ascorbate as cofactors.Succinate competes with α-ketoglutarate in binding to the PHD enzyme.Therefore, increasing α-ketoglutarate levels can offset the effect of succinate accumulation. Normal α-ketoglutarate does not permeate cell walls efficiently, and it is necessary to create a cell permeating derivative (e.g. α-ketoglutarate esters).In-vitro trials show this supplementation approach can reduce HIF1-α levels, and may result in a therapeutic approach to tumours resulting from SDH deficiency. ### Impaired developmental apoptosis Paraganglionic tissue is derived from the neural crest cells present in an embryo.Abdominal extra-adrenal paraganglionic cells secrete catecholamines that play an important role in fetal development.After birth these cells usually die, a process that is triggered by a decline in nerve growth factor (NGF)which initiates apoptosis (cell death). This cell death process is mediated by an enzyme called prolyl hydroxylase EglN3.Succinate accumulation caused by SDH inactivation inhibits the prolyl hydroxylase EglN3.The net result is that paranglionic tissue that would normally die after birth remains, and this tissue may be able to trigger paraganglioma/pheochromocytoma later. ### Glycolysis upregulation Inhibition of the Citric Acid Cycle forces the cell to create ATP glycolytically in order to generate its required energy.The induced glycolytic enzymes could potentially block cell apoptosis. ## RNA editing The mRNA transcripts of the SDHB gene in human are edited through an unknown mechanism at ORF nucleotide position 136 causing the conversion of C to U and thus generating a stop codon resulting in the translation of the edited transcripts to a truncated SDHB protein with an R46X amino acid change.This editing has been shown in monocytes and some human lymphoid cell-lines, and is enhanced by hypoxia. # 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}

SDHC SDHC is an abbrevation for succinate dehydrogenase complex subunit C. The term SDHC can refer to; - The protein subunit itself. - The gene that codes for this protein. The succinate dehydrogenase (SDH) protein complex catalyzes the oxidation of succinate (succinate + ubiquinone => fumarate + ubiquinol).The SDHA subunit is connected to the SDHB subunit on the hydrophilic, catalytic end of the complex.Electrons removed from succinate transfer SDHA, to SDHB and further to the SDHC/SDHD subunits on the hydrophobic end of the complex anchored in the mitochondrial membrane. # Function of the SDHC protein The SDH complex is located on the inner membrane of the mitochondria and participates in both the Citric Acid Cycle and Respiratory chain. SDHC acts as an intermediate in the basic SDH enzyme action: - SDHA converts succinate to fumarate as part of the Citric Acid Cycle.This reaction also converts FAD to FADH2. - Electrons from the FADH2 are transferred to the SDHB subunit iron clusters ,,.This function is part of the Respiratory chain - Finally the electrons are transferred to the Ubiquinone (Q) pool via the SDHC/SDHD subunits. # Gene that codes for SDHC The gene that codes for the SDHC protein is nuclear, even though the protein is located in the inner membrane of the mitochondria.The location of the gene in humans is on the first chromosome at q21.The gene is partitioned in 6 exons. The expressed protein has 170 amino acids. SDHC was previously called PGL3.

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}

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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)

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.

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.

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.

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.

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.

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.

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.

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.

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.

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).

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.

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.

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.

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.

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.

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)

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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). .

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

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.

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..

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).

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

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.

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.

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.

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.

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.

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.

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).

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

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.

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.

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.

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.

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.

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.