The roles of FADD in extrinsic apoptosis and necroptosis [cached]
Eun-Woo Lee1,*, Jinho Seo1, Manhyung Jeong1, Sangsik Lee2 & Jaewhan Song1,*
BMB Reports , 2012,
Abstract: Fas-associated protein with death domain (FADD), an adaptorthat bridges death receptor signaling to the caspase cascade, isindispensible for the induction of extrinsic apoptotic cell death.Interest in the non-apoptotic function of FADD has greatlyincreased due to evidence that FADD-deficient mice ordominant-negative FADD transgenic mice result in embryoniclethality and an immune defect without showing apoptoticfeatures. Numerous studies have suggested that FADD regulatescell cycle progression, proliferation, and autophagy, affectingthese phenomena. Recently, programmed necrosis, also callednecroptosis, was shown to be a key mechanism that inducesembryonic lethality and an immune defect. Supporting thesefindings, FADD was shown to be involved in various necroptosismodels. In this review, we summarize the mechanism ofextrinsic apoptosis and necroptosis, and discuss the in vivo andin vitro roles of FADD in necroptosis induced by various stimuli.
Effect of IRAK1 on Apoptosis and Necroptosis of Hepatoma Cell Line SK-Hep1 [PDF]
Zhijia Pan, Xiaolei Zhang, Changshi Qian, Xiaochen Liu, Xinglin Jin
Chinese Medicine (CM) , 2019, DOI: 10.4236/cm.2019.101003
Abstract: Interleukin I receptor associated kinase 1 (IRAK1) is a downstream signal molecule of activated MyD88 recruitment, which can activate Fas associated death domain protein (FADD) to induce apoptosis. IRAK1 can also activate tumor necrosis factor-related factor 6 (TRAF6) and induce the expression of a series of downstream specific genes. IRAK1 is an essential factor in the induction of mitochondrial division and necroptosis. In the current study, RNAi technique was used to silence IRAK1, and the apoptosis and necroptosis rate of SK-Hep1 cells were detected by flow cytometry. The apoptosis and the necroptosis pathway of hepatoma SK-Hep1 cells were blocked separately, and the expressions of FADD, RIP1 and TRAF6 genes were silenced separately. The results showed when the expression of IRAK1 was down-regulated, the apoptosis and necroptosis rate of SK-Hep1 cells were significantly increased. With silenced FADD, RIP1 and TRAF6, respectively, the expression of IRAK1 protein had no significant change. However, the expression of IRAK1 mRNA decreased significantly (p < 0.01) after the silencing of RIP1 and TRAF6 genes, while the IRAK1 mRNA did not change significantly after the silencing of FADD genes; when z-VAD-FMK was interfered, the expression of IRAK1 mRNA decreased significantly after the silencing of TRAF6 genes, while the IRAK1 mRNA did not change significantly after the silencing of FADD and RIP1genes. The study shows that RAK1 gene inhibits apoptosis and necroptosis in SK-Hep1 cells. TRAF6 gene affected the role of IRAK1 in apoptosis and necroptosis, RIP1 gene affected the role of IRAK1 in apoptosis, while FADD gene did not affect the role of IRAK1 in apoptosis and necroptosis.
Necroptosis: Molecular Signalling and Translational Implications [PDF]
Claudia Giampietri,Donatella Starace,Simonetta Petrungaro,Antonio Filippini,Elio Ziparo
International Journal of Cell Biology , 2014, DOI: 10.1155/2014/490275
Abstract: Necroptosis is a form of programmed necrosis whose molecular players are partially shared with apoptotic cell death. Here we summarize what is known about molecular signalling of necroptosis, particularly focusing on fine tuning of FLIP and IAP proteins in the apoptosis/necroptosis balance. We also emphasize necroptosis involvement in physiological and pathological conditions, particularly in the regulation of immune homeostasis. 1. Introduction In 1998 Vandenabeele's group demonstrated that murine L929 fibrosarcoma cells treated with the pan-caspase inhibitor zVAD-FMK rapidly die in a necrotic way after tumor necrosis factor (TNF) incubation, indicating a possible involvement of caspases in protection against TNF-induced necrosis [1]. Additional works then described this particular form of cell death having many hallmarks of cellular necrosis and induced by death receptor stimulation [2, 3]. Further studies performed by introducing the cowpox virus serpin and caspase-8 inhibitor CrmA in the cells, confirmed that caspase-8 inhibition leads to this form of cell death [4]. Remarkably, while necrosis has been believed in the past to be a passive and accidental form of cell death, it is now considered a finely regulated process [5]. For such a reason it is called necroptosis or programmed necrosis. Necroptosis is characterized by cell swelling, mitochondria dysfunction, plasma membrane permeabilization, and release of cytoplasmic content to the extracellular space. This form of cell death is also associated with high mitochondrial reactive oxygen species (ROS) production and unlike apoptosis it does not involve DNA fragmentation [6]. 2. Necroptosis Activation and Signalling Necroptosis can be activated by members of the tumor necrosis factor (TNF) family (through TNFR1, TNFR2, TRAILR1, and TRAILR2), Fas ligand, toll-like receptors, lipopolysaccharides (LPS), and genotoxic stress [2, 7–9]. Also different kinds of physical-chemical stress stimuli can initiate necroptosis, including anticancer drugs, ionizing radiation, photodynamic therapy, glutamate, and calcium overload [10]. Under conditions that are insufficient to trigger apoptosis, TNFα activates TNFR1 and in turn induces the recruitment of receptor-interacting protein 1 (RIP1) kinase and other proteins to form complex I. Subsequently, these proteins dissociate from TNFR1 and RIP1 can be found in the cytosol in complex IIb, which includes RIP1, receptor-interacting protein 3 (RIP3) kinase, caspase-8 and FADD. The formation of complex IIb leads to necroptosis [11]. Complex I also includes TRADD which is
Apoptosis: A Programmed Cell Death [cached]
Rajiv Dahiya,Devender Pathak
Pharmaceutical Reviews , 2007,
Abstract: Cell death is currrently the subject of considerable research activity. This interest stems from the possibility of exploiting the cell death program for therapeutic purposes. Cell injury can be irreversible or reversible. Apoptosis (pronounced "ay-puh-TOE-sis") is a reversible pathway of cellular "suicide" which usually takes place by two major routes viz. internal / external signals and death deactivators.Moreover, apoptosome and caspases are the vital contributions of programmed cell death. Regulation of this form of cell death comprises of participation of bcl-2 proteins, TP53 gene, nitric oxide as well as steroid hormones. In real sense, apoptosis involves deliberate elimination of cells occuring in a morphologically distinct manner that suggests an active, tightly controlled gene-directed process. Therefore, a single sentence definition for apoptosis comprises 'gene-directed cellular self-destruction'.
Chronicles of a Silent Death: Apoptosis
Research in Cell Biology , 2012, DOI: 10.5923/j.cellbiology.20120101.01
Abstract: In whole human body thousands and thousands of cells are produced by mitosis every second and a similar number dies at the same time through a genetically controlled pathway of cellular self-destruction: apoptosis. The homeostatic balance between proliferation and cell death occur in a finely regulated manner during embryonic development and throughout life. However, this balance is often altered by both internal and/or external agents such as inherited mutations or chemotherapy, respectively; acting like mutagens and providing an unlimited proliferation level where affected cells evade apoptosis and lead cancer. Currently, chemotherapy is the most used strategy for preventing and fight against cancer; nevertheless, it is not specific and it could produce serious side effects including the generation of a second tumor. Activation or reactivation of apoptosis in cancer cells using specific and natural drugs discovered is one of the key alternatives to combat this disease, which occurs in a silent manner and without adverse effects. This review presents the main dramatic features that occur during apoptosis activation and the main proteins, which trigger and inhibits this death pathway.
Shikonin Kills Glioma Cells through Necroptosis Mediated by RIP-1 [PDF]
Chuanjiang Huang, Yinan Luo, Jingwei Zhao, Fuwei Yang, Hongwei Zhao, Wenhai Fan, Pengfei Ge
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0066326
Abstract: Background and Purpose Shikonin was reported to induce necroptosis in leukemia cells, but apoptosis in glioma cell lines. Thus, it is needed to clarify whether shikonin could cause necroptosis in glioma cells and investigate its underlying mechanisms. Methods Shikonin and rat C6 glioma cell line and Human U87 glioma cell line were used in this study. The cellular viability was assayed by MTT. Flow cytometry with annexin V-FITC and PI double staining was used to analyze cellular death modes. Morphological alterations in C6 glioma cells treated with shikoinin were evaluated by electronic transmission microscopy and fluorescence microscopy with Hoechst 33342 and PI double staining. The level of reactive oxygen species was assessed by using redox-sensitive dye DCFH-DA. The expressional level of necroptosis associated protein RIP-1 was analyzed by western blotting. Results Shikonin induced cell death in C6 and U87 glioma cells in a dose and time dependent manner. The cell death in C6 and U87 glioma cells could be inhibited by necroptosis inhibitor necrotatin-1, not by pan-caspase inhibitor z-VAD-fmk. Shikonin treated C6 glioma cells presented electron-lucent cytoplasm, loss of plasma membrane integrity and intact nuclear membrane in morphology. The increased ROS level caused by shikonin was attenuated by necrostatin-1 and blocking ROS by anti-oxidant NAC rescued shikonin-induced cell death in both C6 and U87 glioma cells. Moreover, the expressional level of RIP-1 was up-regulated by shikonin in a dose and time dependent manner as well, but NAC suppressed RIP-1 expression. Conclusions We demonstrated that the cell death caused by shikonin in C6 and U87 glioma cells was mainly via necroptosis. Moreover, not only RIP-1 pathway, but also oxidative stress participated in the activation of shikonin induced necroptosis.
Necroptosis Takes Place in Human Immunodeficiency Virus Type-1 (HIV-1)-Infected CD4+ T Lymphocytes [PDF]
Ting Pan, Shuangxin Wu, Xin He, Haihua Luo, Yijun Zhang, Miaomiao Fan, Guannan Geng, Vivian Clarke Ruiz, Jim Zhang, Lisa Mills, Chuan Bai, Hui Zhang
Abstract: Human immunodeficiency virus type 1 (HIV-1) infection is characterized by progressive depletion of CD4+ T lymphocytes and dysfunction of the immune system. The numbers of CD4+ T lymphocytes in the human body are maintained constantly by homeostatic mechanisms that failed during HIV-1 infection, resulting in progressive loss of CD4+ T cells mainly via apoptosis. Recently, a non-apoptotic form of necrotic programmed cell death, named necroptosis, has been investigated in many biological and pathological processes. We then determine whether HIV-1-infected cells also undergo necroptosis. In this report, we demonstrate that HIV-1 not only induces apoptosis, but also mediates necroptosis in the infected primary CD4+ T lymphocytes and CD4+ T-cell lines. Necroptosis-dependent cytopathic effects are significantly increased in HIV-1-infected Jurkat cells that is lack of Fas-associated protein-containing death domain (FADD), indicating that necroptosis occurs as an alternative cell death mechanism in the absence of apoptosis. Unlike apoptosis, necroptosis mainly occurs in HIV-infected cells and spares bystander damage. Treatment with necrostatin-1(Nec-1), a RIP1 inhibitor that specifically blocks the necroptosis pathway, potently restrains HIV-1-induced cytopathic effect and interestingly, inhibits the formation of HIV-induced syncytia in CD4+ T-cell lines. This suggests that syncytia formation is mediated, at least partially, by necroptosis-related processes. Furthermore, we also found that the HIV-1 infection-augmented tumor necrosis factor-alpha (TNF-α) plays a key role in inducing necroptosis and HIV-1 Envelope and Tat proteins function as its co-factors. Taken together,necroptosis can function as an alternative cell death pathway in lieu of apoptosis during HIV-1 infection, thereby also contributing to HIV-1-induced cytopathic effects. Our results reveal that in addition to apoptosis, necroptosis also plays an important role in HIV-1-induced pathogenesis.
Apoptosis as form of natural ovarian cell death [PDF]
Radovanovi? Anita M.,Stevanovi? Jelka ?.,Gledi? Du?an S.
Veterinarski Glasnik , 2004, DOI: 10.2298/vetgl0402043r
Abstract: Different hormones, cytokines, the absence of growth factors, and others, are some of the signals for initiating apoptosis in ovarian cells. Each of them in its own way, trigger apoptosis as a form of death in which the cell actively participates by precisely implementing a genetically programmed sequence of biochemical and morphological changes which lead to selfdestruction. Apoptosis is a physiological form of death, which helps establish a dynamic balance among proiliferation, differenciation, and death of ovarian cells. It has been confirmed so far that follicular cells oocytes, cells of the germinal epithelium, theca cells, and corpus luteum cells die through apoptosis. The physiological deaths of these cells are an integral part of normal ovarian function, both during intrauterine and postnatal life. Namely, during intrauterine ovarian development, about half the total number of germinative cells (future oocytes) die through apoptosis and their population is gradually reduced after birth by so-called selection of follicles which will continue further growth (folliculogenesis) and the apoptosis of cells of those follicles which will be subjected to atresion. Most ovarian cells die by apoptosis continuously until the end of the reproductive life period of healthy females, and some can continue dieing in this way until the death of the given individual (e.g. germinal epithelium cells).
The Meaning of Death: Evolution and Ecology of Apoptosis in Protozoan Parasites [PDF]
Sarah E. Reece ,Laura C. Pollitt,Nick Colegrave,Andy Gardner
PLOS Pathogens , 2011, DOI: 10.1371/journal.ppat.1002320
Abstract: The discovery that an apoptosis-like, programmed cell death (PCD) occurs in a broad range of protozoan parasites offers novel therapeutic tools to treat some of the most serious infectious diseases of humans, companion animals, wildlife, and livestock. Whilst apoptosis is an essential part of normal development, maintenance, and defence in multicellular organisms, its occurrence in unicellular parasites appears counter-intuitive and has proved highly controversial: according to the Darwinian notion of "survival of the fittest", parasites are expected to evolve strategies to maximise their proliferation, not death. The prevailing, and untested, opinion in the literature is that parasites employ apoptosis to "altruistically" self-regulate the intensity of infection in the host/vector. However, evolutionary theory tells us that at most, this can only be part of the explanation, and other non-mutually exclusive hypotheses must also be tested. Here, we explain the evolutionary concepts that can explain apoptosis in unicellular parasites, highlight the key questions, and outline the approaches required to resolve the controversy over whether parasites "commit suicide". We highlight the need for integration of proximate and functional approaches into an evolutionary framework to understand apoptosis in unicellular parasites. Understanding how, when, and why parasites employ apoptosis is central to targeting this process with interventions that are sustainable in the face of parasite evolution.
Soft SUSY Breaking Grand Unification: Leptons vs Quarks on the Flavor Playground
Ciuchini, M.;Masiero, A.;Paradisi, P.;Silvestrini, L.;Vempati, S. K.;Vives, O.
High Energy Physics - Phenomenology , 2007, DOI: 10.1016/j.nuclphysb.2007.05.032
Abstract: We systematically analyze the correlations between the various leptonic and hadronic flavor violating processes arising in SUSY Grand Unified Theories. Using the GUT-symmetric relations between the soft SUSY breaking parameters, we assess the impact of hadronic and leptonic flavor observables on the SUSY sources of flavor violation.