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)

Signal transduction induced by tumor necrosis factor (TNF) family members and their receptors has been an intensive area of research for several years. The major impact of these studies has been the delineation of apoptotic and cell survival signaling pathways. These discoveries, coupled with major advances in the study of mammalian apoptotic machinery, constitute a promising blueprint of the molecular network governing the fate of all living cells. In this review, we concentrate on the fate of cells in the immune system, where regulation of cell death and cell survival is a frequent and important exercise. A small imbalance in favor of either fate can result in disastrous pathological outcomes, such as cancer, autoimmunity or immune deficiency. It is an insurmountable task to discuss all molecules reported in the literature that are implicated in lymphocyte death or survival. We have therefore focused on discoveries made by mouse gene targeting, as these studies provide the most physiologically relevant information on each molecule. We begin with a description of signaling channels initiated by TNF receptor type 1 engagement, which can lead to either cell survival or to cell death. The point of bifurcation of this pathway and the decision-making molecules FADD, TRAF2 and RIP are discussed. We then follow apoptotic and survival pathways from upstream to downstream, describing many important players involved in signal transduction. Molecules important for NF-kappaB and JNK/stress-activated protein kinase activation such as IKKbeta, NEMO, MAP3K and TRAF6 are discussed, as is the impact of BAFF and its receptors on B-cell survival. Mouse mutants that have helped to define the mammalian apoptosis execution machinery, including animals lacking Apaf-1, caspase-3 and caspase-9, are also described. We conclude with a brief analysis of the potential therapeutic options arising from this body of work.
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PMID:Signaling for survival and apoptosis in the immune system. 1211 Jan 44

Apoptosis has a major role in molding the embryo, in the maintenance of tissue homeostasis, and in the defense against pathogens, while its disgregulation is strongly implicated in cancer as well as in autoimmune and degenerative diseases. The opposite action of anti-apoptotic proteins (Bcl-2 family) and pro-apoptotic proteins (p53, Bax, Bak) regulates the activation of caspases that are the effectors proteases of the cell suicide. Bcl-W is a pro-survival protein, recently discovered, related to the Bcl-2 family. The presence of Bcl-W is fundamental for spermatogenesis in rats. Caspases are cysteine-dependent aspartate-specific proteases, and their over-expression can result in apoptotic cell death. Normally, caspases exist in cells as inactive pro-enzymes and can be activated by 2 distinct mechanisms: the FADD/caspase 8 cascade, and the Apaf-1/caspase 9 cascade. These 2 mechanisms are used extensively by cells for the activation of the effectors caspases: caspase 3, caspase 6, and/or caspase 7. Bcl-W and caspases might have a pivotal role in maintenance of Sertoli cells integrity. In this study, we demonstrate that both Bcl-W mRNA and caspase 3 mRNA are expressed in isolated Sertoli cells of pre-puberal rat testes. This finding might be crucial in clarifying whether Sertoli cells die by an apoptotic mechanism. Further studies are required to understand whether the expression of Bcl-W and caspases is different before and after puberty in rat testis and/or in pathological conditions, that lead to an increased cell apoptosis.
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PMID:RNA expression bcl-w, a new related protein Bcl-2 family, and caspase-3 in isolated sertoli cells from pre-pubertal rat testes. 1215 Mar 48

Death induced by doxorubicin (dox) in neuroblastoma (NB) cells was originally thought to occur via the Fas pathway, however since studies suggest that caspase-8 expression is silenced in most high stage NB tumors, it is more probable that dox-induced death occurs via a different mechanism. Caspase-8 silenced N-type invasive NB cell lines LAN-1 and IMR-32 were investigated for their sensitivity to dox, and compared to S-type noninvasive SH-EP NB cells expressing caspase-8. All cell lines had similar sensitivities to dox, independently of caspase-8 expression. Dox induced caspase-3, -7, -8 and -9 and Bid cleavage in S-type cells and death was blocked by caspase inhibitors but not by oxygen radical scavenger BHA. In contrast, dox-induced death in N-type cells was caspase-independent and was inhibited by BHA. Dox induced a drop in mitochondrial membrane permeability in all cell lines. Dox-induced death in S-type cells gave rise to apoptotic nuclei, whereas in N-type cells nuclei were non-apoptotic in morphology. Transfection of SH-EP cells with a dominant negative FADD mutant inhibited TRAIL-induced death, but had no effect on dox-induced apoptosis. These results suggest that S-type cells undergo apoptosis after dox treatment independently of death receptors, whereas N-type cells are killed by a caspase-independent mechanism.
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PMID:Doxorubicin-induced death in neuroblastoma does not involve death receptors in S-type cells and is caspase-independent in N-type cells. 1220 25

Previous studies by our laboratory have shown that the drug transporter protein P-glycoprotein, P-gp, can specifically inhibit Fas-induced caspase-3 activation and apoptosis. Importantly, inhibition of both caspase-3 activation and cell death could be reversed by pharmacological and antibody inhibitors of P-gp function. However, the molecular mechanisms underpinning P-gp-mediated resistance to Fas-induced cell death and caspase activation remained unknown. We therefore sought to identify the point(s) within the death receptor pathway at which P-gp exerted its inhibitory effect and to determine whether the ATPase activity of P-gp was required. Structure-function analysis determined that ATP hydrolysis was necessary for P-gp to confer resistance to Fas-induced caspase activation and cell death. Importantly, although both FADD and caspase-8 were recruited to the Death Inducing Signal Complex (DISC) in wild-type P-gp expressing cells following Fas ligation, subsequent activation of caspase-8 at the DISC was inhibited. The ability of P-gp to inhibit caspase-8 activation was also ATP dependent. These studies demonstrate that P-gp inhibits Fas-induced caspase-8 activation but not formation of the DISC and that this activity of P-gp is dependent on ATP hydrolysis.
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PMID:P-glycoprotein inhibits caspase-8 activation but not formation of the death inducing signal complex (disc) following Fas ligation. 1240 26

Bile acids induce hepatocyte injury by enhancing death receptor-mediated apoptosis. In this study, bile acid effects on TRAIL-mediated apoptosis were examined to gain insight into bile acid potentiation of death receptor signaling. TRAIL-induced apoptosis of HuH-7 cells, stably transfected with a bile acid transporter, was enhanced by bile acids. Caspase 8 and 10 activation, bid cleavage, cytosolic cytochrome c, and caspase 3 activation by TRAIL were all increased by the bile acid glycochenodeoxycholate (GCDCA). GCDCA (100 microm) did not alter expression of TRAIL-R1/DR4, TRAIL-R2/DR5, procaspase 8, cFLIP-L, cFLIP-s, Bax, Bcl-xL, or Bax. However, both caspase 8 and caspase 10 recruitment and processing within the TRAIL death-inducing signaling complex (DISC) were greater in GCDCA-treated cells whereas recruitment of cFLIP long and short was reduced. GCDCA stimulated phosphorylation of both cFLIP isoforms, which was associated with decreased binding to GST-FADD. The protein kinase C antagonist chelerythrine prevented bile acid-stimulated cFLIP-L and -s phosphorylation, restored cFLIP binding to GST-FADD, and attenuated bile acid potentiation of TRAIL-induced apoptosis. These results provide new insights into the mechanisms of bile acid cytotoxicity and the proapoptotic effects of cFLIP phosphorylation in TRAIL signaling.
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PMID:Bile acids stimulate cFLIP phosphorylation enhancing TRAIL-mediated apoptosis. 1240

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a wide range of malignant cells. However, several cancers, including human hepatoma, are resistant to TRAIL. In this study, we analyzed TRAIL-induced pro- and antiapoptotic signaling pathways in human hepatoma cells. Nuclear factor kappa B (NF-kappaB) was found to be a critical TRAIL-induced antiapoptotic factor in the PLC/PRF/5, HepG2, and Hep3B cell lines. TRAIL-induced NF-kappaB activation was preceded by IkappaBalpha kinase (IKK) activation and IkappaBalpha degradation and depended on TRAF2, NF-kappaB-inducing kinase (NIK), IKK1, and IKK2. Accordingly, inhibition of NF-kappaB by adenoviral dominant negative (dn) TRAF2, NIKdn, IKK1dn, IKK2dn, or IkappaBsr sensitized PLC/PRF/5 cells to rhTRAIL, resulting in 40% to 50% cell death after 48 hours as compared with <10% with rhTRAIL alone. Agonistic anti-TRAIL receptor 1 and anti-TRAIL receptor 2 antibodies or combinations of both were equally efficient in inducing apoptosis as rhTRAIL, indicating that decoy receptors did not contribute to resistance toward TRAIL under the conditions of our study. TRAIL-mediated apoptosis depended on FADD, caspase 8 and 3 as demonstrated by the ability of FADDdn, CrmA, and pharmacologic caspase inhibitors to prevent apoptosis. Confocal microscopy showed the onset of the mitochondrial permeability transition (MPT) 5 hours after rhTRAIL plus actinomycin D, which was followed by cytochrome c release. The MPT was critical for TRAIL-induced apoptosis as demonstrated by the ability of pharmacologic MPT inhibitors to completely protect PLC/PRF/5 cells. In conclusion, NF-kappaB prevents TRAIL-induced apoptosis in human hepatoma through a TRAIL-activated TRAF2-NIK-IKK pathway. Inhibition of NF-kappaB unmasks a TRAIL-induced apoptotic signaling cascade that involves FADD, caspase 8, the MPT, and caspase 3.
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PMID:TRAIL-mediated apoptosis requires NF-kappaB inhibition and the mitochondrial permeability transition in human hepatoma cells. 1244 76

The proinflammatory cytokine IL-4 is secreted in large amounts during allergic inflammatory response in asthma and plays a pivotal role in the airway inflammation. IL-4 has been shown to up-regulate 15-lipoxygenase and produce 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) in A549 cells via the Janus kinase/STAT6 pathway under coactivation of CREB binding protein/p300. IL-4 has also been shown to up-regulate peroxisome proliferator-activated receptor gamma (PPARgamma) nuclear receptors in macrophages and A549 cells. In this study we demonstrate that 15(S)-HETE binds to PPARgamma nuclear receptors and induces apoptosis in A549 cells. Moreover, pretreatment of cells with nordihydroguaiaretic acid, a 15-lipoxygenase inhibitor, prevented PPARgamma activation and apoptosis. The latter was accomplished by the interaction of the 15(S)-HETE/PPARgamma complex with the adapter protein Fas-associating protein with death domain and caspase-8, as shown by transfection of Fas-associating protein with death domain dominant negative vector and cleavage of caspase 8 to active subunits p41/42 and p18. Whereas IL-4 and PPARgamma ligands failed to induce cleavage of Bid and release of cytochrome c from mitochondria, they caused translocation of the proapoptotic protein Bax from cytoplasm to mitochondria with a concomitant decrease in the Bcl-x(L) level. We therefore believe that in unstimulated cells Bcl-x(L) and Bax form a heterodimer, in which Bcl-x(L) dominates and prevents the induction of apoptosis, whereas in IL-4-stimulated cells the 15(S)-HETE/PPARgamma complex down-regulates Bcl-x(L), and the resulting overweight of Bax commits the cell to apoptosis via caspase-3. However, this pathway does not rule out the direct caspase-8-mediated activation of caspase-3. In conclusion, IL-4-induced apoptosis may contribute to severe loss of alveolar structures and infiltration of eosinophils, mononuclear phagocytes, etc., into the lung tissue of chronic asthma patients.
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PMID:IL-4 induces apoptosis in A549 lung adenocarcinoma cells: evidence for the pivotal role of 15-hydroxyeicosatetraenoic acid binding to activated peroxisome proliferator-activated receptor gamma transcription factor. 1251 54

Excess ER stress induces caspase-12 activation and/or cytochrome c release, causing caspase-9 activation. Little is known about their relationship during ER stress-mediated cell death. Upon ER stress, P19 embryonal carcinoma (EC) cells showed activation of various caspases, including caspase-3, caspase-8, caspase-9, and caspase-12, and extensive DNA fragmentation. We examined the relationship between ER stress-mediated cytochrome c/caspase-9 and caspase-12 activation by using caspase-9- and caspase-8-deficient mouse embryonic fibroblasts and a P19 EC cell clone [P19-36/12 (-) cells] lacking expression of caspase-12. Caspase-9 and caspase-8 deficiency inhibited and delayed the onset of DNA fragmentation but did not inhibit caspase-12 processing induced by ER stress. P19-36/12 (-) cells underwent apoptosis upon ER stress, with cytochrome c release and caspase-8 and caspase-9 activation. The dominant negative form of FADD and z-VAD-fmk inhibited caspase-8, caspase-9, Bid processing, cytochrome c release, and DNA fragmentation induced by ER stress, suggesting that caspase-8 and caspase-9 are the main caspases involved in ER stress-mediated apoptosis of P19-36/12 (-) cells. Caspase-8 deficiency also inhibited the cytochrome c release induced by ER stress. Thus, in parallel with the caspase-12 activation, ER stress triggers caspase-8 activation, resulting in cytochrome c/caspase-9 activation via Bid processing.
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PMID:ER stress induces caspase-8 activation, stimulating cytochrome c release and caspase-9 activation. 1258 36

Preclinical studies in animal models and human clinical trials have evaluated the safety and efficacy of adenoviral vectors for cancer gene therapy. These studies have indicated that gene delivery via adenoviral vectors, including p53 gene therapy, represents a promising therapeutic modality for many types of human cancers. This review focuses on novel strategies to induce apoptosis in glioma cells by transduction with adenoviral vectors carrying a variety of apoptosis-related genes, including Fas ligand, Fas, FADD, caspase-8, p53, p33ING1, p73alpha, Bax, Apaf-1, caspase-9, IkappaBdN, caspase-3, Bcl-2, and Bcl-X(L). We conclude that adenoviral vector-mediated delivery of apoptosis-related genes other than p53 is a potentially useful gene therapy approach toward the treatment of human brain tumors.
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PMID:Gene therapy using an adenovirus vector for apoptosis-related genes is a highly effective therapeutic modality for killing glioma cells. 1265 7

Controversy has surrounded a role for apoptosis in the loss of neurons in Parkinson's disease (PD). Although a variety of evidence has supported an apoptotic contribution to PD neuronal loss particularly in the nigra, two factors have weighed against general acceptance: (1) limitations in the use of in situ 3' end labeling techniques to demonstrate nuclear DNA cleavage; and (2) the insistence that a specific set of nuclear morphological features be present before apoptotic death could be declared. We first review the molecular events that underlie apoptotic nuclear degradation and the literature regarding the unreliability of 3' DNA end labeling as a marker of apoptotic nuclear degradation. Recent findings regarding the multiple caspase-dependent or caspase-independent signaling pathways that mediate apoptotic nuclear degradation and determine the morphological features of apoptotic nuclear degradation are presented. The evidence shows that a single nuclear morphology is not sufficient to identify apoptosis and that a cytochrome c, pro-caspase 9, and caspase 3 pathways is operative in PD nigral apoptosis. BAX-dependent increases in mitochondrial membrane permeability are responsible for the release of mitochondrial factors that signal for apoptotic degradation, and increased BAX levels have been found in a subset of PD nigral neurons. Studies using immunocytochemistry in PD postmortem nigra have begun to define the premitochondrial apoptosis signaling pathways in the disease. Two, possibly interdependent, pathways have been uncovered: (1) a p53-glyceraldehyde-3-phosphate dehydrogenase (GAPDH)-BAX pathway; and (2) FAS receptor-FADD-caspase 8-BAX pathway. Based on the above, it seems unlikely that apoptosis does not contribute to PD neuronal loss, and the definition of the premitochondrial signaling pathways may allow for the development and testing of an apoptosis-based PD therapy.
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PMID:Apoptosis in Parkinson's disease: signals for neuronal degradation. 1266 99


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