Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Histone deacetylase activity is potently inhibited by hydroaximc acid derivatives such as suberoylanilide hydroxamic acid (SAHA) and trichostatin-A (TSA). These inhibitors specifically induce differentiation/apoptosis of transformed cells in vitro and suppress tumor growth in vivo. Because of its low toxicity, SAHA is currently evaluated in clinical trials for the treatment of cancer. SAHA and TSA induce apoptosis, which is characterized by mitochondrial stress, but so far, the critical elements of this apoptotic program remain poorly defined. To characterize in more detail this apoptotic program, we used human cell lines containing alterations in important elements of apoptotic response such as: p53, Bcl-2, caspase-9, and caspase-3. We demonstrate that caspase-9 is critical for apoptosis induced by SAHA and TSA and that efficient proteolytic activation of caspase-2, caspase-8, and caspase-7 strictly depends on caspase-9. Bcl-2 efficiently antagonizes cytochrome c release and apoptosis in response to both histone deacetylase inhibitors. We provide evidences that translocation into the mitochondria of the Bcl-2 family member Bid depends on caspase-9 and that this translocation is a late event during TSA-induced apoptosis. We also demonstrate that the susceptibility to TSA- and SAHA-induced cell death is regulated by p53.
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PMID:Role of caspases, Bid, and p53 in the apoptotic response triggered by histone deacetylase inhibitors trichostatin-A (TSA) and suberoylanilide hydroxamic acid (SAHA). 1255 48

Proteolytic activation of initiator procaspases is a crucial step in the cellular commitment to apoptosis. Alternative models have been postulated for the activation mechanism, namely the oligomerization or induced proximity model and the allosteric regulation model. While the former holds that procaspases become activated upon proper oligomerization by an adaptor protein, the latter states that the adaptor is an allosteric regulator for procaspases. The allosteric regulation model has been applied for the activation of procaspase-9 by apoptotic protease-activating factor (Apaf-1) in an oligomeric complex known as the apoptosome. Using approaches that allow for controlled oligomerization, we show here that aggregation of multiple procaspase-9 molecules can induce their activation independent of the apoptosome. Oligomerization-induced procaspase-9 activation, both within the apoptosome and in artificial systems, requires stable homophilic association of the protease domains, raising the possibility that the function of Apaf-1 is not only to oligomerize procaspase-9 but also to maintain the interaction of the caspase-9 protease domain after processing. In addition, we provide biochemical evidence that other apoptosis initiator caspases (caspase-2 and -10) as well as a procaspase involved in inflammation (murine caspase-11) are also activated by oligomerization. Thus, oligomerization of precursor molecules appears to be a general mechanism for the activation of both apoptosis initiator and inflammatory procaspases.
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PMID:Oligomerization is a general mechanism for the activation of apoptosis initiator and inflammatory procaspases. 1263 14

It has been difficult to assign caspase-2 to the effector or initiator caspase groups. It bears sequence homology to initiators (caspase-9 and CED-3), but its cleavage specificity is closer to the effectors (caspase-3 and -7). Interest in caspase-2 was dampened by the lack of a dramatic phenotype in the caspase-2 null mouse. Studies have been inhibited by the lack of knowledge about its mechanism of activation and the lack of specific methods to assay its activity. Molecular studies have defined a unique role for caspase-2 in apoptosis initiated by beta-amyloid toxicity or by trophic factor deprivation. Recently, a role for caspase-2 as an upstream initiator of mitochondrial permeabilization has been proposed. Thus, while much remains to be deciphered about caspase-2, most critically the mode of activation, it is clear that caspase-2 plays critical and singular roles in the control of programmed cell death.
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PMID:Caspase-2 redux. 1265 98

Both the anticancer agent 2-chloro-2'-deoxy-adenosine (Cladribine) and its derivative 2-chloro-adenosine induce apoptosis of human astrocytoma cells (J Neurosci Res 60:388-400, 2000). In this study, we have analyzed the involvement of caspases in these effects. Both compounds produced a gradual and time-dependent activation of "effector" caspase-3, which preceded the appearance of the nuclear signs of apoptosis, suggesting a temporal correlation between these two events. Moreover, the caspase inhibitor N-benzyloxycarbonyl-Val-Ala-dl-Asp-fluoromethylketone (fmk) suppressed both caspase-3 activation and apoptosis induction. "Initiator" caspase-9 and caspase-8 were only marginally activated at later times in the apoptotic process. Accordingly, at concentrations that selectively inhibit these caspases, neither N-benzyloxycarbonyl-Leu-Glu-His-Asp-fmk nor N-benzyloxycarbonyl-Ile-Glu-Thr-Asp-fmk could prevent adenosine analog-induced cell death. To definitively rule out a role for the caspase-9/cytochrome c-dependent mitochondrial pathway of cell death, neither adenosine analog had any effect on mitochondrial membrane potential, which was instead markedly reduced by other apoptotic stimuli (e.g., deoxyribose, NaCN, and betulinic acid). Consistently, although the latter triggered translocation of mitochondrial cytochrome c to the cytoplasm, no cytosolic accumulation of cytochrome c was detected with adenosine analogs. Conversely, 1 to 7 h after addition of either adenosine analog (i.e., before the appearance of caspase-3 activation), caspase-2 activity was surprisingly and markedly increased. The selective caspase-2 inhibitor N-benzyloxy carbonyl-Val-Asp-Val-Ala-Asp-fmk significantly reduced both adenosine analogs-induced caspase-2 activation and the associated cell death. We conclude that adenosine analogs induce the apoptosis of human astrocytoma cells by activating an atypical apoptotic cascade involving caspase-2 as an initiator caspase, and effector caspase-3. Therefore, these compounds could be effectively used in the pharmacological manipulation of tumors characterized by resistance to cell death via either the mitochondrial or caspase-8/death receptor pathways.
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PMID:A key role for caspase-2 and caspase-3 in the apoptosis induced by 2-chloro-2'-deoxy-adenosine (cladribine) and 2-chloro-adenosine in human astrocytoma cells. 1276 55

Oxidized low-density lipoproteins (oxLDL) play a critical role in atherogenesis. One oxidative pathway of LDL involves myeloperoxidase, which catalyzes the production of hypochlorous acid (HOCl) in monocytes. We investigated the apoptotic mechanism induced by oxLDL, generated by HOCl treatment of native LDL, in human monocytic U937 cell line. The involvement of the mitochondrial apoptotic pathway was analyzed in Bcl-2-overexpressing clones, generated from U937 cells. HOCl-oxLDL induced in U937 cells (i) a marked caspase-dependent increase of apoptosis, (ii) a loss of mitochondrial membrane potential, (iii) a specific activation of caspase-2, -3, -8, and -9, and (iv) a similar degree of apoptosis in presence or absence of anti-Fas and anti-TNF-R1 antibodies. Moreover, the degree of HOCl-oxLDL-induced caspase-3 and -8 activation, and apoptosis was significantly reduced in U937/Bcl-2 cells, with no activation of caspase-9. By contrast, Cu-oxLDL-mediated apoptosis in U937 cells involved exclusively the mitochondrial pathway. In conclusion, the mechanism of HOCl-oxLDL-induced apoptosis in monocytic U937 cells involves the two pathways of apical caspase activation: (i) death receptor-mediated caspase-8 and (ii) mitochondria-mediated caspase-9. This converges in the activation of executing caspases, including caspase-3, and apoptosis. The interference of Bcl-2 overexpression with HOCl-oxLDL-induced apoptosis suggests the importance of mitochondrial involvement in this apoptotic mechanism.
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PMID:Apoptotic pathways involved in U937 cells exposed to LDL oxidized by hypochlorous acid. 1295 53

There has been a considerable debate as to whether caspase-2 is an initiator or effector caspase. Recently, a new model of intrinsic pathway of apoptosis has been proposed, which suggests caspase-2 to be an initiator caspase. For example, ultraviolet radiation (UV) and other DNA damage-inducing agents were shown to first activate caspase-2 and then regulate the mitochondrial and postmitochondrial events. Active caspase-2 was found to engage mitochondria by promoting Bax translocation to the mitochondria. Consequently, Bax was proposed to play a central role in bridging the active caspase-2 with mitochondria by affecting mitochondrial permeability, cytochrome c release into the cytosol and caspase-9 activation. In the present study, we investigated the role of Bax in UV-induced apoptosis and caspase-2 activation. Our results indicate that UV-induced apoptosis and caspase-2 activation were diminished in Bax-deficient cells, suggesting that Bax appears to play an important role in UV-induced apoptosis as well as caspase-2 activation, and that it also appears to reside upstream of caspase-2. Bax deficiency also affected the activation of caspase-3 and -8 and abolished caspase-9 activation during UV-induced apoptosis, suggesting that the absence of caspase-9 activation may affect caspase-2, -3 and -8 activation in Bax-deficient cells. Based on our results, we propose that activation of caspases is not a linear cascade of events, but is rather connected via complex feedback loops.
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PMID:Bax deficiency affects caspase-2 activation during ultraviolet radiation-induced apoptosis. 1464 55

The mitochondrial death pathway is triggered in cultured sympathetic neurons by deprivation of nerve growth factor (NGF), but the death mechanisms activated by deprivation of other neurotrophic factors are poorly studied. We compared sympathetic neurons deprived of NGF to those deprived of glial cell line-derived neurotrophic factor (GDNF). In contrast to NGF-deprived neurons, GDNF-deprived neurons did not die via the mitochondrial pathway. Indeed, cytochrome c was not released to the cytosol; Bax and caspase-9 and -3 were not involved; overexpressed Bcl-xL did not block the death; and the mitochondrial ultrastructure was not changed. Similarly to NGF-deprived neurons, the death induced by GDNF removal is associated with increased autophagy and requires multiple lineage kinases, c-Jun and caspase-2 and -7. Serine 73 of c-Jun was phosphorylated in both NGF- and GDNF-deprived neurons, whereas serine 63 was phosphorylated only in NGF-deprived neurons. In many NGF-deprived neurons, the ultrastructure of the mitochondria was changed. Thus, a novel nonmitochondrial caspase-dependent death pathway is activated in GDNF-deprived sympathetic neurons.
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PMID:GDNF-deprived sympathetic neurons die via a novel nonmitochondrial pathway. 1465 32

The marine alkaloid ascididemin (ASC) was shown to exert cytotoxicity even against multidrug-resistant cancer cells. Here, we address the signaling pathways utilized by ASC to trigger apoptosis in Jurkat leukemia T cells. We show that ASC (0.5-20 microM) induces a mitochondrial pathway that requires the activation of the initiator caspase-2 upstream of mitochondria. ASC-triggered apoptosis occurred independent of CD95, but required mitochondrial dysfunction. The activation of caspase-2 was shown to precede the processing of caspase-8, -9 and -3. The specific caspase-2 inhibitor zVDVADfmk abrogated ASC-induced DNA fragmentation almost completely. Overexpression of Bcl-x(L) blocked caspase-8 but not caspase-2 processing. Conversely, caspase-2 inhibition strongly reduced caspase-9 activation. As a possible link between caspase-2 and mitochondrial dysfunction, Bid was found to be cleaved by ASC. In addition, JNK was activated by ASC upstream of mitochondria via reactive oxygen species. The specific JNK inhibitor SP600125 partially inhibited caspase-2 and -9 processing as well as cytochrome c release and DNA fragmentation indicating that JNK contributes to, but is not necessary for ASC-mediated apoptosis. Thus, ASC triggers a pathway in which early activation of caspase-2 provides a possible link between its DNA-damaging activity and the induction of mitochondrial dysfunction. The activation of JNK contributes to this signaling upstream of mitochondria.
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PMID:Apoptosis signaling triggered by the marine alkaloid ascididemin is routed via caspase-2 and JNK to mitochondria. 1471

We recently demonstrated that reperfusion rapidly induces the mitochondrial pathway of apoptosis in chick cardiomyocytes after 1 h of simulated ischemia. Here we tested whether ischemia-reperfusion (I/R)-induced apoptosis could be initiated by caspase-dependent cytochrome c release in this model of cardiomyocyte injury. Fluorometric assays of caspase activity showed little, if any, activation of caspases above baseline levels induced by 1 h of ischemia alone. However, these assays revealed rapid activation of caspase-2, yielding a 2.95 +/- 0.52-fold increase (over ischemia only) within the 1st h of reperfusion, whereas activities of caspases-3, -8, and -9 increased only slightly from their baseline levels. The rapid and prominent activation of caspase-2 suggested that it could be an important initiator caspase in this model, and using specific caspase inhibitors given only at the point of reperfusion, we tested this hypothesis. The caspase-2 inhibitor benzyloxycarbonyl-Val-Asp(Ome)-Val-Ala-Asp(Ome)-CH(2)F was the only caspase inhibitor that significantly inhibited cytochrome c release from mitochondria. This inhibitor also completely blocked activation of caspases-3, -8, and -9. The caspase-3/7 inhibitor transiently and only partially blocked caspase-2 activity and was less effective in blocking the activities of caspases-8 and -9. The caspase-8 inhibitor failed to significantly block caspase-2 or -3, and the caspase-9 inhibitor blocked only caspase-9. Furthermore, the caspase-2 inhibitor protected against I/R-induced cell death, but the caspase-8 inhibitor failed to do so. These data suggest that active caspase-2 initiates cytochrome c release after reperfusion and that it is critical for the I/R-induced apoptosis in this model.
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PMID:Caspase-dependent cytochrome c release and cell death in chick cardiomyocytes after simulated ischemia-reperfusion. 1497 33

Previous studies suggest the protective potentiality of Ginkgo biloba (EGb 761) against apoptotic cell death induced by hydroxyl radicals, staurosporine, serum deprivation and beta-amyloid (betaA) peptide. We have extended these observations to cultured cortical neurons and studied the effect of EGb 761 on neuronal survival (evaluated as MTT reduction), the presence of condensed nuclei (monitored as Hoechst staining), the time-course of caspase-1, caspase-3 and caspase-9 activation (measured by cleavage of specific fluorescent substrates) and superoxide anion production (evaluated by hydroethidine staining) after the exposure to staurosporine. Results show that 200 microg/ml of EGb 761 increased cell survival and reduced the number of condensed nuclei after the exposure to 200 nM staurosporine. Vitamin E and the spin trapper alpha-phenyl-N-tert-butylnitrone (PBN) also significantly increased cell survival. In contrast, the broad-spectrum caspase inhibitors ZVAD and ZBIOT showed no protection. Similarly, selective inhibitors of caspase-1 (YVAD-CHO), caspase-2 (VDVAD-CHO), caspase-3 (DEVD-CHO) and caspase-8 (IETD-CHO) did not protect against cell damage induced by staurosporine. The protective effect of EGb 761 was not enhanced when coincubated with vitamin E or DEVD-CHO. Caspase-3 activity was maximally induced 5-8 h after staurosporine exposure. Both EGb 761 and vitamin E showed a tendency to decrease caspase-3 activity. In contrast, activation of caspase-1 and caspase-9 was not observed at any of the times studied after STS exposure. Exposure to staurosporine resulted in increased superoxide production that was maximal at 5 h. EGb 761 significantly inhibited superoxide production at short times after staurosporine exposure. Vitamin E and PBN also significantly reduced superoxide production. Results suggest that EGb 761 neuroprotective effect might be mediated by its well-known antioxidant activity, which might also influence caspase-3 activation. Inhibition of capase-3 induced by EGb 761 and vitamin E does not seem to contribute to their observed protective action.
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PMID:Effect of Ginkgo biloba (EGb 761) on staurosporine-induced neuronal death and caspase activity in cortical cultured neurons. 1498 36


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