Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.61 (caspase-8)
 6,833 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

ASK1 activates JNK and p38 mitogen-activated protein kinases and constitutes a pivotal signaling pathway in cytokine- and stress-induced apoptosis. However, little is known about the mechanism of how ASK1 executes apoptosis. Here we investigated the roles of caspases and mitochondria in ASK1-induced apoptosis. We found that benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (zVAD-fmk), a broad-spectrum caspase inhibitor, mostly inhibited ASK1-induced cell death, suggesting that caspases are required for ASK1-induced apoptosis. Overexpression of ASK1DeltaN, a constitutively active mutant of ASK1, induced cytochrome c release from mitochondria and activation of caspase-9 and caspase-3 but not of caspase-8-like proteases. Consistently, caspase-8-deficient (Casp8 (-/-)) cells were sensitive to ASK1-induced caspase-3 activation and apoptosis, suggesting that caspase-8 is dispensable for ASK1-induced apoptosis, whereas ASK1 failed to activate caspase-3 in caspase-9-dificient (Casp9 (-/-)) cells. Moreover, mitochondrial cytochrome c release, which was not inhibited by zVAD-fmk, preceded the onset of caspase-3 activation and cell death induced by ASK1. ASK1 thus appears to execute apoptosis mainly by the mitochondria-dependent caspase activation.
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PMID:Execution of apoptosis signal-regulating kinase 1 (ASK1)-induced apoptosis by the mitochondria-dependent caspase activation. 1084 26

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor family and has recently been shown to exert tumoricidal activity in vivo in the absence of any observable toxicity. The signaling pathways triggered by TRAIL stimulation and the mechanisms involved in resistance against TRAIL-mediated apoptosis are still poorly defined. We show here that TRAIL-induced apoptosis involves late dissipation of mitochondrial membrane potential (delta psi(m)) and cytochrome c release. These events follow activation of caspase-8 and caspase-3 and induction of DNA fragmentation. In addition, caspase-8-deficient cells are resistant against TRAIL-induced apoptosis, and inhibition of caspase-8 but not caspase-9 prevents mitochondrial permeability transition and apoptosis. In contrast, various Bcl-2- or Bcl-xL-overexpressing tumor cell lines are sensitive to TRAIL-induced apoptosis; however, they show a delay in TRAIL-induced mitochondrial permeability transition compared with control transfectants. This indicates that TRAIL-induced apoptosis depends on caspase-8 activation rather than on the disruption of mitochondrial integrity. Because most chemotherapeutic drugs used in the treatment of malignancies lead to apoptosis primarily by engagement of the mitochondrial proapoptotic machinery, we tested whether drug-resistant tumor cells retain sensitivity for TRAIL-induced apoptosis. Tumor cells overexpressing Bcl-2 or Bcl-xL become resistant to apoptosis induced by the chemotherapeutic drug etoposide. However, these cells are not protected or are only marginally protected against TRAIL-induced apoptosis. Thus, TRAIL may still kill tumors that have acquired resistance to chemotherapeutic drugs by overexpression of Bcl-2 or Bcl-xL. These data will influence future treatment strategies involving TRAIL.
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PMID:Tumor necrosis factor-related apoptosis-inducing ligand retains its apoptosis-inducing capacity on Bcl-2- or Bcl-xL-overexpressing chemotherapy-resistant tumor cells. 1085 Apr 56

We previously reported that exposure of DiFi human colon cancer cells to the anti-epidermal growth factor (EGF) receptor monoclonal antibody (mAb) 225 resulted in apoptosis, but the mechanisms remain to be elucidated. In the present study, we investigated the effects of a panel of four anti-EGF receptor mAbs, each of which binds to different epitopes of the EGF receptor in DiFi cells, on the induction of apoptosis. We found that each of these mAbs induced apoptosis in DiFi cells. Exposure of DiFi cells to mAb 225 activated the initiation caspase-8, which was detectable between 8 and 16 h after exposure of the cells to the antibody. There was also an activation of the initiation caspase-9, which lagged a few hours behind the activation of caspase-8. Exposure of DiFi cells to mAb 225 also activated the execution caspase-3, which was accompanied temporally by evidence of cleavage of a well-characterized caspase-3 substrate, poly(ADP)ribosepolymerase (PARP). Pre-exposure of the cells to the caspase-3-specific inhibitor DEVD-CHO partially reduced the mAb 225-induced PARP cleavage and apoptosis, whereas pre-exposure of the cells to the caspase pan-inhibitor z-VAD-fmk completely inhibited mAb 225-induced apoptosis. Caspases-3, -8 and -9 were not activated in the cell lines in which mAb 225 only induced G1 phase arrest of the cell cycle. In contrast to the apoptosis of DiFi cells induced by ultraviolet irradiation, which strongly activated the c-jun N-terminal kinase-1 (JNK1) and the caspase cascade, mAb 225-induced apoptosis and activation of the caspase cascade in DiFi cells were not associated with activation of JNK1.
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PMID:Induction of apoptosis and activation of the caspase cascade by anti-EGF receptor monoclonal antibodies in DiFi human colon cancer cells do not involve the c-jun N-terminal kinase activity. 1086 8

Caspases are aspartate-specific proteases that are specifically activated by numerous death stimuli. Caspase activation is thought to play a major role for the execution of apoptosis. Inactive caspase-9 zymogen is known to be localized within the mitochondrial intermembrane space where it is involved in monitoring mitochondrial damage-associated cytochrome c release and subsequent activation of procaspase-3. Here we show that in mammary epithelial cell lines a significant fraction of caspase-9 proform is associated with discrete structures in the nucleus. Stimulation of cells with chemotherapeutic agents leads to the processing of nuclear procaspase-9 and to the accumulation of nuclear and cytoplasmic caspase activity. Using cell-free extracts from caspase-3-deficient MCF-7 cells we show that caspase-8-mediated processing of nuclear procaspase-9 requires caspase-3. In caspase-3-expressing breast cancer cells, cytochrome c-induced processing of nuclear procaspase-9 is blocked by the caspase inhibitors z-VAD and DEVD but not by YVAD. Purified active caspase-3 is sufficient to cleave nuclear caspase-9 zymogen. These results suggest that, in addition to the mitochondrial localization, caspase-9 proform is found within the nucleus and its processing can be regulated by caspase-3.
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PMID:Nuclear localization of procaspase-9 and processing by a caspase-3-like activity in mammary epithelial cells. 1088 67

Zinc-chelating agents, including ethambutol and its metabolite 2,2'(ethylenediamino)-dibutyric acid (EDBA) are toxic to retinal ganglion cells through a glutamate dependent mechanism. We explored whether such cell death was mediated through the caspase family of cysteine proteases. Retinal cultures were treated with EDBA alone, or EDBA plus a variety of known caspase inhibitors, and ganglion cell viability was assayed. EDBA killed 20-30% of ganglion cells. A general caspase inhibitor, BAF, prevented EDBA induced ganglion cell death. Specific inhibitors of caspase-3 and caspase-6 showed a similar ability to BAF in preventing EDBA mediated ganglion cell loss, whereas inhibitors of caspase-8 and caspase-9 were not able to rescue EDBA treated ganglion cells. A caspase-1,4 inhibitor was less effective than BAF. These studies show that a caspase mediated mechanism of apoptosis accents for a portion of EDBA mediated retinal ganglion cell death. This toxicity was mediated by downstream effector caspases, 3 and 6. Caspase inhibitors may prevent ganglion cell death secondary to ethambutol treatment.
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PMID:Caspase inhibitors block zinc-chelator induced death of retinal ganglion cells. 1092 89

The IAP (inhibitor of apoptosis) family of anti-apoptotic proteins regulates programmed cell death. Of the six known human IAP-related proteins, XIAP is the most potent inhibitor. To study the mechanistic effects of XIAP on DNA damage-induced apoptosis, we prepared U-937 cells that stably overexpress XIAP. The results demonstrate that XIAP inhibits apoptosis induced by 1-[beta-d-arabinofuranosyl]cytosine (ara-C) and other genotoxic agents. XIAP had no detectable effect on ara-C-induced release of mitochondrial cytochrome c and attenuated cleavage of procaspase-9. In addition, we show that ara-C induces the association of XIAP with the cleaved fragments of caspase-9 and thereby inhibition of caspase-9 activity. The results also demonstrate that ara-C induces cleavage of procaspase-3 by a caspase-8-dependent mechanism and that XIAP inhibits caspase-3 activity. These results demonstrate that XIAP functions downstream of procaspase-9 cleavage as an inhibitor of both proteolytically processed caspase-9 and -3 in the cellular response to genotoxic stress.
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PMID:XIAP regulates DNA damage-induced apoptosis downstream of caspase-9 cleavage. 1093 Apr 19

Glucagon and the glucagon-like peptides regulate metabolic functions via signaling through a glucagon receptor subfamily of G protein-coupled receptors. Activation of glucagon-like peptide-2 receptor (GLP-2R) signaling maintains the integrity of the intestinal epithelial mucosa via regulation of crypt cell proliferation. Because GLP-2 decreases mortality and reduces intestinal apoptosis in rodents after experimental injury, we examined whether GLP-2R signaling directly modifies the cellular response to external injury. We show here that activation of GLP-2R signaling inhibits cycloheximide-induced apoptosis in baby hamster kidney fibroblasts expressing a transfected GLP-2 receptor. GLP-2 reduced DNA fragmentation and improved cell survival, in association with reduced activation of caspase-3 and decreased poly(ADP-ribose) polymerase cleavage and reduced caspase-8 and caspase-9-like activities. Both GLP-2 and forskolin reduced mitochondrial cytochrome c release and decreased the cycloheximide-induced cleavage of caspase-3 in the presence or absence of the PKA inhibitor H-89. Similarly, GLP-2 increased cell survival following cycloheximide in the presence of the kinase inhibitors PD98054 and LY294002. These findings provide evidence that signaling through G protein-coupled receptors of the glucagon superfamily is directly linked to regulation of apoptosis and suggest the existence of a cAMP-dependent protein kinase-, phosphatidylinositol 3-kinase-, and mitogen-activated protein kinase-independent pathway coupling GLP-2R signaling to caspase inhibition and cell survival.
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PMID:The glucagon-like peptide-2 receptor mediates direct inhibition of cellular apoptosis via a cAMP-dependent protein kinase-independent pathway. 1094 Mar 5

The adenovirus E1B 19K gene product is an inhibitor of apoptosis induced by tumor necrosis factor-alpha (TNF-alpha) during viral infection. We report that E1B 19K inhibited neither caspase-8 activation nor caspase-8-dependent Bid cleavage by TNF-alpha. Rather, TNF-alpha induced a tBid-dependent conformational change in Bax that allowed an interaction between E1B 19K and conformationally altered Bax, which caused inhibition of cytochrome c release and caspase-9 activation. E1B 19K expression interrupted caspase-3 processing, permitting cleavage to remove the p12 subunit but not the prodomain consistent with caspase-8 and not caspase-9 enzymatic activity. Thus, E1B 19K blocks TNF-alpha-mediated death signaling by inhibiting a specific form of Bax that interrupts caspase activation downstream of caspase-8 and upstream of caspase-9.
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PMID:TNF-alpha signals apoptosis through a bid-dependent conformational change in Bax that is inhibited by E1B 19K. 1094 27

We investigated the mechanism of mitomycin C (MMC)-induced apoptosis in SNU-16 human gastric adenocarcinoma cells. Caspase-8 and caspase-3 were activated in MMC-treated cells whereas caspase-1 was not activated, and cytochrome c was released from mitochondrial membrane to cytosol suggesting that caspase-9 was activated during the MMC-induced apoptotic process. Protein kinase C (PKC) delta was cleaved to its characteristic 40 kDa fragment in a caspase-3-dependent manner; on the other hand PKC zeta was cleaved to approximately 40 kDa independently of caspase-3 in the drug-induced apoptosis of the cells. Incubation with z-DEVD-fmk and benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD-fmk) almost completely abrogated MMC-induced DNA fragmentation, indicating that activation of these caspases was crucially involved in MMC-induced apoptosis. Activation of caspase-8 in response to Fas triggering by recruitment of caspase-8 to the Fas has also been found, however, MMC did not induce FasL and Fas expression, as evidenced by reverse transcriptase-polymerase chain reaction and Western blotting. Taken together, these findings indicate that MMC-induced apoptosis in SNU-16 cells was mediated by caspase-8, caspase-9, and caspase-3 activation independently of FasL/Fas interactions.
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PMID:Mitomycin C induces apoptosis in a caspases-dependent and Fas/CD95-independent manner in human gastric adenocarcinoma cells. 1096 Jul 61

Recently, apoptosis (genetically programmed cell death) induced by UV has been documented in some cell culture models. However, the significance of apoptosis in UV-induced cytotoxicity and resistance is uncertain. In this study, we investigated the induction of apoptosis in HeLa cells and its role in acquired UV-resistance. The membrane receptor Fas was induced to assembly, and its immediate downstream target, caspase-8, was induced by UV in a dose- and time-dependent manner. Caspase-10, another possible candidate for forming the death-inducing signaling complex with Fas, was also activated in a dose- and time-dependent manner. There was significant activation of caspase 9, 3 and 2 by UV. The apoptotic pathways appeared to be normal in acquired UV-resistant HeLa cells. In addition, there was a UV dose-dependent induction of chromatin condensation in both parental and UV-resistant cells. However, resistant cells displayed significant reduction in chromatin condensation at lower doses. Inhibition of caspase-3 activation by specific inhibitor significantly reduced the chromatin condensation in both cell types, and unexpectedly, the difference between the two cell lines was completely eradicated, suggesting that the caspase-3 pathway plays a significant role in reducing apoptosis in resistant cells. The results indicate that UV induces apoptosis by direct activation of apoptotic proteins in HeLa and resistant cells. Although resistant cells displayed partial inhibition of UV-induced apoptosis through the caspase-3 pathway, there was no consistent difference in the activation of this and related caspase-9 caspases compared to parental HeLa cells.
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PMID:UV-induced apoptosis in resistant HeLa cells. 1096 67


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