Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.22.62 (caspase-9)
 7,507 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanism(s) of c-Myc transcription factor-induced apoptosis is still obscure. The activation of c-Myc has been found to lead into the processing/activation of caspases (caspase-3), but the significance of this for the cell demise is debatable. Here we report that several targets of caspases (PKCdelta, MDM2, PARP, replication factor C, 70 kDa U1snRNP, fodrin and lamins) are cleaved during c-Myc-induced apoptosis in Rat-1 MycER cells, indicating an important role for caspases in the apoptotic process. We further found that the ATM (ataxia telangiectasia mutated)--protein is a novel key substrate of caspases. In in vitro assays, purified recombinant ATM protein was found to be cleaved by the effector caspases 3 and 7. The functional significance of the ATM cleavage is supported by the finding that ectopic expression of ATM protected in part against apoptosis. We also show that c-Myc-induced apoptosis involves loss of mitochondrial transmembrane potential, release of cytochrome c from mitochondria into the cytosol and subsequent processing of caspase-9. The cleavage of caspase-9 is, however, minimal and a much later event than the processing/activation of caspase-3, suggesting that it is not the apical caspase. Evidence is provided that there is, nevertheless, an upstream caspase(s) regulating the functions of caspase-3 and mitochondria. Additionally, it was found that p53 becomes upregulated, together with its transcriptional targets MDM2 and p21, upon c-Myc induction, but this occurs also at a later time than the activation of caspase-3.
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PMID:Caspases and mitochondria in c-Myc-induced apoptosis: identification of ATM as a new target of caspases. 1082 87

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

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

The endocannabinoid anandamide (AEA) is shown to induce apoptotic bodies formation and DNA fragmentation, hallmarks of programmed cell death, in human neuroblastoma CHP100 and lymphoma U937 cells. RNA and protein synthesis inhibitors like actinomycin D and cycloheximide reduced to one-fifth the number of apoptotic bodies induced by AEA, whereas the AEA transporter inhibitor AM404 or the AEA hydrolase inhibitor ATFMK significantly increased the number of dying cells. Furthermore, specific antagonists of cannabinoid or vanilloid receptors potentiated or inhibited cell death induced by AEA, respectively. Other endocannabinoids such as 2-arachidonoylglycerol, linoleoylethanolamide, oleoylethanolamide, and palmitoylethanolamide did not promote cell death under the same experimental conditions. The formation of apoptotic bodies induced by AEA was paralleled by increases in intracellular calcium (3-fold over the controls), mitochondrial uncoupling (6-fold), and cytochrome c release (3-fold). The intracellular calcium chelator EGTA-AM reduced the number of apoptotic bodies to 40% of the controls, and electrotransferred anti-cytochrome c monoclonal antibodies fully prevented apoptosis induced by AEA. Moreover, 5-lipoxygenase inhibitors 5,8,11,14-eicosatetraynoic acid and MK886, cyclooxygenase inhibitor indomethacin, caspase-3 and caspase-9 inhibitors Z-DEVD-FMK and Z-LEHD-FMK, but not nitric oxide synthase inhibitor Nomega-nitro-l-arginine methyl ester, significantly reduced the cell death-inducing effect of AEA. The data presented indicate a protective role of cannabinoid receptors against apoptosis induced by AEA via vanilloid receptors.
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PMID:Anandamide induces apoptosis in human cells via vanilloid receptors. Evidence for a protective role of cannabinoid receptors. 1091 56

Suppression of the gastrin gene in human colon cancer cells by stably expressing antisense (AS) gastrin RNA results in significant growth suppression of AS cells. To understand mechanisms mediating the growth effects of autocrine gastrins, differential expression of transcripts by AS and control (C) clones of a representative cell line (HCT-116) was analyzed to identify target genes of autocrine gastrins. Six differentially expressed transcripts were confirmed and sequenced. Of these, the RNA and protein levels of cytochrome c oxidase (COX) Vb were significantly higher in C versus AS cells. The expression of COX Vb by colon cancer cells was proportional to the expression of gastrin. Higher levels of COX Vb coprecipitated with cytochrome c in the mitochondria of C versus AS cells. Treatment of mitochondria with digitonin resulted in a 2-fold higher release of cytochrome c from AS versus C mitochondria. As a corollary, the cytosolic levels of cytochrome c were significantly higher in AS versus C cells, which correlated with approximately 2- and approximately 3-fold higher activation of caspase-9 and -3, respectively, in AS versus C cells in response to camptothecin. Thus, autocrine gastrins may support growth/survival of cells by up-regulating COX Vb, which may decrease the sensitivity of the cancer cells to apoptotic stimuli by increasing retention of cytochrome c in mitochondria.
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PMID:Autocrine gastrins in colon cancer cells Up-regulate cytochrome c oxidase Vb and down-regulate efflux of cytochrome c and activation of caspase-3. 1091 81

We report here the identification of a novel protein, Smac, which promotes caspase activation in the cytochrome c/Apaf-1/caspase-9 pathway. Smac promotes caspase-9 activation by binding to inhibitor of apoptosis proteins, IAPs, and removing their inhibitory activity. Smac is normally a mitochondrial protein but is released into the cytosol when cells undergo apoptosis. Mitochondrial import and cleavage of its signal peptide are required for Smac to gain its apoptotic activity. Overexpression of Smac increases cells' sensitivity to apoptotic stimuli. Smac is the second mitochondrial protein, along with cytochrome c, that promotes apoptosis by activating caspases.
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PMID:Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. 1092 11

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

Ebselen, a selenoorganic compound, has recently been shown to display a novel property of inducing apoptosis through rapid depletion of intracellular thiols in human hepatoma cells, HepG(2). The present study was thus designed to explore the mechanism of how ebselen triggers apoptosis upon depletion of intracellular thiols. The results demonstrated that ebselen treatment triggered mitochondrial permeability transition rather rapidly as revealed by redistribution of calcein green fluorescence from cytosol into mitochondria. Ebselen treatment also caused a dose- and time-dependent loss of mitochondrial membrane potential (MMP) and release of cytochrome c. Pretreatment with N-acetylcysteine, a precursor of intracellular reduced glutathione (GSH) synthesis, significantly attenuated the ebselen-induced MMP disruption and subsequently inhibited the apoptosis. In contrast, pretreatment with buthionine sulfoximine, a specific inhibitor of intracellular GSH synthesis, significantly augmented the ebselen-induced MMP alteration, and enhanced the apoptosis. Although ebselen treatment significantly increased the intracellular superoxide radical and calcium concentrations, superoxide dismutase, and BAPTA (a calcium chelator), however, failed to prevent ebselen-induced MMP loss and apoptosis. Neither caspase-9 nor caspase-3 activation was detected in ebselen-treated cells. Z-VAD-FMK, a general caspase inhibitor, also had no effect on ebselen-induced MMP decrease and apoptosis. The overall findings thus suggest that mitochondrial permeability transition resulted from intracellular thiol depletion is a critical event in ebselen-induced apoptosis.
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PMID:Intracellular thiol depletion causes mitochondrial permeability transition in ebselen-induced apoptosis. 1093 87

Release of cytochrome c from mitochondria by apoptotic signals induces ATP/dATP-dependent formation of the oligomeric Apaf-1-caspase-9 apoptosome. Here we show that the documented anti-apoptotic effect of the principal heat-shock protein, Hsp70, is mediated through its direct association with the caspase-recruitment domain (CARD) of Apaf-1 and through inhibition of apoptosome formation. The interaction between Hsp70 and Apaf-1 prevents oligomerization of Apaf-1 and association of Apaf-1 with procaspase-9. On the basis of these results, we propose that resistance to apoptosis exhibited by stressed cells and some tumours, which constitutively express high levels of Hsp70, may be due in part to modulation of Apaf-1 function by Hsp70.
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PMID:Negative regulation of the Apaf-1 apoptosome by Hsp70. 1093 67


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