Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apoptosis is a genetically programmed cell death that is required for morphogenesis during embryogenic development and for tissue homeostasis in adult organisms. In most cases, apoptosis involves cytochrome c release from mitochondria. In the cytosol, cytochrome c combines with APAF-1 in the presence of ATP to activate caspase-9 that, in turn, activates effectors caspases such as caspase-3. Bcl-2 and related proteins control cytochrome c release from the mitochondria whereas IAP (for Inhibitor of APoptosis) molecules modulate the activity of caspases. Plasma membrane receptors such as Fas (CD95, APO-1), characterized by a so-called "death domain" in their cytoplasmic domain, can activate the caspase cascade through adaptator molecules such as FADD (Fas-Associated protein with a Death Domain). Dysregulation of the apoptotic machinery plays a role in the pathogenesis of various diseases and molecules involved in cell death pathways are potential therapeutic targets in immunologic, neurologic, cancer, infectious and inflammatory diseases.
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PMID:[Apoptosis: molecular mechanisms]. 1010 3

We report here the reconstitution of the de novo procaspase-9 activation pathway using highly purified cytochrome c, recombinant APAF-1, and recombinant procaspase-9. APAF-1 binds and hydrolyzes ATP or dATP to ADP or dADP, respectively. The hydrolysis of ATP/dATP and the binding of cytochrome c promote APAF-1 oligomerization, forming a large multimeric APAF-1.cytochrome c complex. Such a complex can be isolated using gel filtration chromatography and is by itself sufficient to recruit and activate procaspase-9. The stoichiometric ratio of procaspase-9 to APAF-1 is approximately 1 to 1 in the complex. Once activated, caspase-9 disassociates from the complex and becomes available to cleave and activate downstream caspases such as caspase-3.
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PMID:An APAF-1.cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9. 1020 61

Apoptosis and platelet activation share common morphological and biochemical features. Because caspases are essential mediators of apoptosis, we examined whether platelets contain these proteinases and use them during platelet activation. Human platelets contained caspase-9, caspase-3, and the caspase activators APAF-1 and cytochrome c as shown by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blotting. Upon treatment with cytochrome c and dATP, platelet cytoplasmic extracts recapitulated apoptotic events, including sequential activation of procaspase-9 and procaspase-3 and subsequent proteolysis of caspase substrates. Calcium ionophore-stimulated platelets also recapitulated apoptotic events, including cell shrinkage, plasma membrane microvesiculation, phosphatidyl serine externalization, and proteolysis of procaspase-9, procaspase-3, gelsolin, and protein kinase C-delta. Strikingly, however, these events occurred without caspase activation or release of mitochondrial cytochrome c, suggesting a role for a noncaspase proteinase. Supporting this, inhibition of the calcium-dependent proteinase, calpain, prevented caspase proteolysis, 'apoptotic' substrate cleavage, and platelet microvesiculation. In vitro, purified calpain cleaved recombinant procaspase-9 and procaspase-3 without activating either caspase, confirming the inhibitor studies. These data implicate calpain as a potential regulator of caspases and suggest that calpain, not caspases, promotes apoptosis-like events during platelet activation.
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PMID:Calpain functions in a caspase-independent manner to promote apoptosis-like events during platelet activation. 1047 93

Cytogenetic and molecular analyses have shown that the chromosome band 12q22 is recurrently deleted in male germ cell tumors (GCTs), indicating the presence of a candidate tumor suppressor gene (TSG) in this region. To identify the TSG, we mapped the APAF1 gene, a proapoptotic mammalian homologue of ced-4, to chromosomal band 12q22, that suggested that this might be the candidate deleted gene in GCTs. We further localized the gene between the polymorphic markers D12S1671 and D12S1082 at 12q22 to determine the role of APAF1 in the pathogenesis of GCT, and we characterized its normal genomic structure and analyzed its alterations in GCTs. The APAF1 gene comprises 27 exons, with the coding region spanning 26. The region containing APAF1 was found to be deleted in GCT by fluorescence in situ hybridization analysis, but without evidence of coding sequence alterations. RT-PCR and Western blot analysis showed APAF1 gene expression at detectable levels in all GCT cell lines analyzed. An aberrant-sized APAF1 protein was seen in one cell line. This and 2 other cell lines carrying APAF1 deletions also exhibited defects in dATP-mediated caspase-3 activation. Caspase-3 activity was effectively restored by addition of recombinant caspase-9 and APAF1 proteins, and to a lesser extent by caspase-9 alone, but not by APAF1 alone. These data do not support a TSG role for APAF1, but defects in other components of the apoptotic pathway that may be related to 12q22 deletion cannot be ruled out. Genes Chromosomes Cancer 28:258-268, 2000.
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PMID:Genetic analysis of the APAF1 gene in male germ cell tumors. 1086 31

Activation of protein kinase C (PKC) by TPA in human U937 myeloid leukemia cells is associated with induction of adherence, differentiation, and G0/G1 cell cycle arrest. In this study, we demonstrate that in addition to these differentiating cells about 25% of U937 cells accumulated in the subG1 phase after TPA treatment. This effect proved to be phorbol ester-specific, since other compounds such as retinoic acid or vitamin D3 failed to induce apoptosis in conjunction with differentiation. Only a specific inhibitor of PKC, GF109203X, but not the broad-spectrum kinase inhibitor staurosporine or a tyrosine kinase inhibitor genistein could reverse the induction of apoptosis. Bryostatin-1, another specific PKC activator with distinct biochemical activity failed to induce apoptosis. Moreover, bryostatin-1 completely abolished the induction of apoptosis in U937 cells even if added 8 hours after TPA treatment. Apart from apoptosis induced by various chemotherapeutic drugs, TPA-related cell death is not mediated by an autocrine Fas-FasL loop and could not be prevented by a blocking antibody to the Fas receptor. However, a 75% reduction in the number of apoptotic cells after TPA stimulation was achieved by preincubation with a blocking antibody to the TNFalpha receptor. Tetrapeptide cleavage assays revealed a four-fold increase in the DEVD-cleavage activity in U937 cells compared to a three-fold increase in TUR cells. Immunoblotting demonstrated that TUR cells did not activate significant levels of caspase-3 or -7, whereas in U937 cells a 20-kDa cleavage product corresponding to activated caspase-3 was detectable after 3 d TPA exposure. Moreover, immunoblots revealed a strongly reduced expression of the adaptor molecule APAF-1, which is required for cytochrome c-dependent activation of caspase-9 and subsequently caspase-3. APAF-1 proved to be inducible after PKC activation with phorbol ester in U937, but not in TUR cells. Thus, APAF-1 expression may, at least in part, be regulated by PKC activity and reduced APAF-1 levels are associated with resistance to various inducers of apoptosis. Furthermore, TPA exposure of U937 cells is associated with increased levels of the pro-apoptotic proteins Bak and Bcl-xs, whereas simultaneously a decline in the Bcl-2 expression was noticable.
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PMID:Protein kinase C activation modulates pro- and anti-apoptotic signaling pathways. 1113 46

Apoptosis is the mode of photoreceptor cell death in many retinal dystrophies. Exposure of Balb/c mice to excessive levels of light induces photoreceptor apoptosis and represents an animal model for the study of retinal degenerations. Caspases have emerged as central regulators of apoptosis, executing this tightly controlled death pathway in many cells. Previously we have reported that light-induced photoreceptor apoptosis occurs independently of one the key executioners of apoptosis, caspase-3. This present study extends these results reporting on the lack of activation of other caspases in this model including caspases-8, -9, -7, and -1. Furthermore, photoreceptor apoptosis cannot be inhibited with the broad range caspase inhibitor zVAD-fmk indicating that light-induced retinal degeneration is caspase-independent. We demonstrate that cytochrome c does not translocate from mitochondria to the cytosol during photoreceptor apoptosis. We also show that during retinal development apoptotic protease activating factor (Apaf-1) protein levels are markedly decreased and this is associated with the inability to activate the mitochondrial caspase cascade in the mature retina. In addition, there is also a significant reduction in expression of caspases-3 and -9 during retinal maturation and these levels do not increase following light exposure. Finally, we show that the calcium-dependent proteases calpains are active during light-induced retinal degeneration and establish that the calcium channel blocker D-cis-diltiazem completely inhibits photoreceptor apoptosis.
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PMID:Caspase-independent photoreceptor apoptosis in vivo and differential expression of apoptotic protease activating factor-1 and caspase-3 during retinal development. 1240 21

Induction and execution of apoptosis programs are generally believed to be mediated through a hierarchy of caspase activation. By using two cellular variants obtained from the L1210 cell line (L1210/S and L1210/0), we have shown previously that staurosporine induces apoptotic cell death through both caspase-dependent and caspase-independent pathways. Both pathways normally coexisted in L1210/S cells, whereas L1210/0 cells lacked the ability to activate caspases despite the confirmed presence of both procaspase-3 and -9. Here we show that this defect in caspase activation is not due to mechanisms such as an absence of cytochrome c release, the expression of non-functional caspases, or the presence of an endogenous inhibitor but results from the loss of apoptosis protease activator protein-1 (APAF-1) expression. This absence of APAF-1 protein results from multiple alterations at both genomic and transcriptional levels. However, although this lack of APAF-1 delays the apoptotic program, it does not hamper its execution. Importantly, in these cells, apoptosis develops not only in an APAF-1-independent way but also in the absence of caspase-3 and -9 activation. Altogether these findings provide evidence that apoptosis may occur through alternative signaling pathways independent of APAF-1 expression and totally dissociated from any caspase processing. Therefore, the L1210/0 variant sub-line provides a valuable tool for the elucidation of these pathways.
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PMID:Apoptosome-independent pathway for apoptosis. Biochemical analysis of APAF-1 defects and biological outcomes. 1277 31

The role of p75 neurotrophin receptor (p75NTR) in mediating cell death is now well characterized, however, it is only recently that details of the death signaling pathway have become clearer. This review focuses on the importance of the juxtamembrane Chopper domain region of p75NTR in this process. Evidence supporting the involvement of K+ efflux, the apoptosome (caspase-9, apoptosis activating factor-1, APAF-1, and Bcl-xL), caspase-3, c-jun kinase, and p53 in the p75NTR cell death pathway is discussed and regulatory roles for the p75NTR ectodomain and death domain are proposed. The role of synaptic activity is also discussed, in particular the importance of neutrotransmitter-activated K+ channels acting as the gatekeepers of cell survival decisions during development and in neurodegenerative conditions.
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PMID:The role of neurotransmission and the Chopper domain in p75 neurotrophin receptor death signaling. 1469 55

In this paper, we examine the hypothesis that 4-hydroxynonenal (HNE), a product of lipid peroxidation, is a key mediator of cell death resulting from beta-amyloid exposure. We revisit the effects of HNE on different neuronal cell types to determine which caspase or caspases are required for HNE-induced death, and to compare these results with the known caspase requirements in other death paradigms. We have previously shown that in a given neuronal cell type different death stimuli can evoke stimulus-specific apoptotic pathways. We now show that HNE treatment of neuronal cells induced dose-dependent death and caspase activity which were blocked by inhibition of caspases. Antisense down-regulation of caspases-3, -7 or -9 provided complete protection from HNE-induced death, as did down-regulation of the caspase regulators APAF-1 and DIABLO. Conversely, this work and our previous studies of three other death paradigms show that caspase-3 is not required for death induced by beta-amyloid, SOD1 down-regulation, or trophic factor deprivation. We also show that HNE accumulated in settings where death does not ensue. We conclude that HNE toxicity is mediated via a caspase-9-dependent pathway but that HNE accumulation need not induce cell death nor is it an obligate mediator of Abeta-induced cell death.
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PMID:Divergence of the apoptotic pathways induced by 4-hydroxynonenal and amyloid beta-protein. 1521 31

The adenine deoxynucleosides cladribine (2CdA) and fludarabine (FAraA) are DNA-damaging agents that interfere with DNA repair and induce apoptosis in nonproliferating lymphoid cells. Although both drugs are clinically used for the treatment of indolent lymphoproliferative diseases, the pathways of apoptosis induction remain largely unknown. In the present work, we demonstrate that both drugs induce apoptosis independently of death receptor signaling but activate the mitochondrial cell death pathway. To dissect the signaling pathways, we employed Jurkat cells either deficient for FADD or caspase-8 or overexpressing Bcl-2. In Bcl-2 overexpressing cells, apoptosis and cytochrome c release were blocked whereas processing of caspase-9, -3 and -8 was partially inhibited. In contrast, neither the deficiency of FADD or caspase-8 nor the interference with death receptor signaling by neutralizing anti-CD95/Fas antibodies affected cell death. Inhibitor experiments revealed that caspase-8 is processed by caspase-3-like caspases. Moreover, cytochrome c release and processing of caspase-9 and -3 occurred to an equal extent in wild-type FADD -/- and caspase-8 -/- Jurkat cells. Likewise, apoptosis induction by cladribine or fludarabine was not hampered upon inhibition of caspase-8 in MOLT-3 and MOLT-4 cells or overexpression of a dominant-negative FADD mutant in BJAB cells. Thus, we conclude that apoptosis induced by nucleoside analogues is independent from death receptor signaling as well as from a proposed direct effect on APAF-1, but rather follows the mitochondrial signaling pathway of cytochrome c release and subsequent processing of caspase-9 and -3.
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PMID:Adenine deoxynucleotides fludarabine and cladribine induce apoptosis in a CD95/Fas receptor, FADD and caspase-8-independent manner by activation of the mitochondrial cell death pathway. 1551 89


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