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:3.4.22.56 (caspase-3)
35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The interleukin 1beta converting enzyme (ICE) family plays a pivotal role in programmed cell death and has been implicated in stroke and neurodegenerative diseases. During reperfusion after filamentous middle cerebral artery occlusion, ICE-like cleavage products and tissue immunoreactive interleukin 1beta (IL-1beta) levels increased in ischemic mouse brain. Ischemic injury decreased after intracerebroventricular injections of ICE-like protease inhibitors, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD.FMK), acetyl-Tyr-Val-Ala-Asp-chloromethylketone, or a relatively selective inhibitor of CPP32-like caspases, N-benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone, but not a cathepsin B inhibitor, N-benzyloxycarbonyl-Phe-Ala-fluoromethylketone. z-VAD.FMK decreased ICE-like cleavage products and tissue immunoreactive IL-1beta levels in ischemic mouse brain and reduced tissue damage when administered to rats as well. Only z-VAD.FMK and acetyl-Tyr-Val-Ala-Asp-chloromethylketone reduced brain swelling, and N-benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone did not attenuate the ischemia-induced increase in tissue IL-1beta levels. The three cysteine protease inhibitors significantly improved behavioral deficits, thereby showing that functional recovery of ischemic neuronal tissue can follow blockade of enzymes associated with apoptotic cell death. Finally, we examined the effect of z-VAD.FMK on excitotoxicity and found that it protected against alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate-induced or to a lesser extent N-methyl-D-aspartate-induced excitotoxic brain damage. Thus, ICE-like and CPP32-like caspases contribute to mechanisms of cell death in ischemic and excitotoxic brain injury and provide therapeutic targets for stroke and neurodegenerative brain damage.
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PMID:Inhibition of interleukin 1beta converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage. 905 Aug 95

The interleukin-1 beta converting enzyme (ICE) family of cysteine proteases has been implicated in apoptosis. This study tested the effects of a novel pan-ICE family inhibitor, bocaspartyl(OMe)-fluoromethylketone (boc-Asp-CH2F), against low potassium-induced apoptosis of cultured rat cerebellar granule neurons (CGN). A single application of this cell-permeant compound (20 microM) inhibited apoptotic cell death up to 48 h. Classical apoptotic changes were monitored by fluorescence microscopy, DNA fragmentation and scanning electron microscopy (SEM). A control peptidic fluoromethylketone (boc-Thr-CH2F), and inhibitors to calpain (Ac-Leu-Leu-norleucinal), cathepsin B (Z-Phe-Ala-CH2F), and CPP32-like proteases (Z-DEVD-CH2F), failed to prevent apoptotic death. An 35S-methionine incorporation assay verified that, unlike cycloheximide, boc-Asp-CH2F did not inhibit protein synthesis, hence excluding this as a rescuing mechanism. Although ICE was not detected by northern blot analysis, both CPP32 and Nedd2 expression were found to increase during apoptosis. Kinetic assays with cell extracts from boc-Asp-CH2F-treated neurons measured reduced rates of cleavage for DEVD-pNA and LEVD-pNA. At present, ICE-like proteases remain viable candidates for mediating neuronal death.
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PMID:Inhibition of the interleukin-1 beta converting enzyme family rescues neurons from apoptotic death. 915 87

PC12 cells undergo apoptosis when cultured under conditions of serum deprivation. In this situation, the activity of caspase-3-like proteinases was elevated, and the survival rate could be maintained by treatment with acetyl-DEVD-cho, a specific inhibitor of caspase-3. In a culture of PC12 cells treated with acetyl-DEVD-cho, where caspase-3-like proteinases are not activated, CA074, a specific inhibitor of cathepsin B induced active death of the cells. Cathepsin B antisense oligonucleotides showed a similar effect to CA074 on the induction of active cell death. By double staining of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling and activated caspase-3, the dying cells treated with CA074 were positive for terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling staining but negative for activated caspase-3. Ultrastructurally, the cells were relatively large and had nuclei with chromatin condensation. The initiation of cell death by CA074 or the cathepsin B antisense were inhibited by the addition of pepstatin A, a lysosomal aspartic proteinase inhibitor, or by cathepsin D antisense. To examine whether this cell death pathway was present in cell types other than PC12 cells, we analysed dorsal root ganglion neurons obtained from rat embryos on the 15th gestational day, a time when they require nerve growth factor for survival and differentiation in culture. When cultured in the absence of nerve growth factor, the neurons survived in the presence of acetyl-DEVD-cho or acetyl-YVAD-cho. Under these conditions, CA074 reduced the survival rate of the neurons, which was subsequently restored by the further addition of pepstain A. These results suggest that a novel pathway for initiating cell death exists which is regulated by lysosomal cathepsins, and in which cathepsin D acts as a death factor. We speculate that this death-inducing activity is normally suppressed by cathepsin B.
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PMID:Regulation of a novel pathway for cell death by lysosomal aspartic and cysteine proteinases. 1033 74

Studies with mouse leukemia L1210 cells revealed that selective lysosomal photodamage caused by any of three photosensitizing agents was followed by a gradual loss of the mitochondrial membrane potential (delta psi m), release of cytochrome c into the cytosol, increased DEVDase activity (a measure of levels of caspase-3) and a limited apoptotic response. Similar effects were observed in the murine hepatoma 1c1c7 cell line. Immunofluorescence techniques employing 1c1c7 cells demonstrated the immediate release of the lysosomal enzyme cathepsin B following lysosomal photodamage. These studies suggest that the cytotoxic effects of lysosomal photodamage are initiated by released lysosomal proteases that either directly and/or indirectly activate caspases as a consequence of the induction of mitochondrial damage.
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PMID:Determinants of the apoptotic response to lysosomal photodamage. 1068 94

A previous paper from this laboratory reported the activation of a caspase-3-like protease by a digitonin-treated lysosomal fraction [FEBS Lett. 435, 233-236, 1998]. In this study, we examined the effects of specific inhibitors of lysosomal cysteine proteases, such as cathepsins B, S, and L, on the activation of caspase-3 to find out which cathepsin is responsible for the activation. Pro-caspase-3 in the cytosol was cleaved by a lysosomal protease(s) contained in the supernatant of a digitonin-treated crude mitochondrial fraction containing lysosomes (ML) and the cleaved product was detected by Western blotting using anti-caspase-3 antibody. The activation of caspase-3 by the lysosomal protease(s) was pH dependent and the optimum pH for activation was pH 6.6-6.8. This activation was not inhibited by CA-074, a specific inhibitor of cathepsin B, but was strongly inhibited by CLIK-066 and CLIK-181, specific inhibitors of cathepsin L. The inhibitory effect of CLIK-060, a specific inhibitor of cathepsin S, was very weak. Furthermore, the activation of caspase-3 was enhanced by addition of purified cathepsin L only in the presence of the supernatant of the digitonin-treated ML. These results suggested that a cathepsin L-type protease activity might participate in the activation mechanism of caspase-3 in the presence of the supernatnat from the ML.
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PMID:Participation of a cathepsin L-type protease in the activation of caspase-3. 1069 61

Cross-linking of the Ag receptors on the immature B cell lymphoma, WEHI-231, leads to growth arrest and apoptosis. We now show that although commitment to such B cell receptor (BCR)-mediated apoptosis correlates with mitochondrial phospholipase A(2) activation, disruption of mitochondrial function, and ATP depletion, it is executed independently of caspase activation. First, we demonstrate a pivotal role for mitochondrial function in determining B cell fate by showing up-regulation of cytosolic phospholipase A(2) expression, induction of mitochondrial phospholipase A(2) activity, arachidonic acid-mediated collapse of mitochondrial transmembrane inner potential (Delta psi(m)), and depletion of cellular ATP under conditions of apoptotic, but not proliferative, signaling via the BCR. Importantly, disruption of Delta psi(m), ATP depletion, and apoptosis can be prevented by rescue signals via CD40 or by Delta psi(m) stabilizers such as antimycin or oligomycin. Second, we show that commitment and postmitochondrial execution of BCR-mediated apoptosis are not dependent on caspase activation by demonstrating that such apoptotic signaling does not induce release of cytochrome c from the mitochondria or activation of effector caspases, as evidenced by poly(ADP-ribose) polymerase or Bcl-x(L) cleavage. Indeed, apoptotic signaling via the BCR in WEHI-231 B cells does not stimulate the activation of caspase-3 and, consistent with this, BCR-mediated disruption of Delta psi(m) and commitment to apoptosis take place in the presence of caspase inhibitors. In contrast, BCR signaling induces the postmitochondrial activation of cathepsin B, and resultant apoptosis is blocked by the cathepsin B inhibitor, (23,35)trans-epoxysuccinyl-L-leucylamindo-3-methylbutane ethyl ester (EST) suggesting a key role for this executioner protease in Ag receptor-driven apoptosis of WEHI-231 immature B cells.
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PMID:B cell receptor-stimulated mitochondrial phospholipase A2 activation and resultant disruption of mitochondrial membrane potential correlate with the induction of apoptosis in WEHI-231 B cells. 1112 86

The deoxyadenosine-resistant mouse leukemia L1210 cell line (Y8) has previously been shown to have phenotypic differences that appear to be unrelated to the altered properties observed at the level of ribonucleotide reductase (RR). One of these changes is that the Y8 cells do not express p53. In response to DNA damaging agents, x-irradiation and doxorubicin, both the parental wild-type L1210 (WT) and Y8 cells undergo G2/M arrest, which is consistent with cells lacking wild-type p53 function. However, Y8 cells are much more sensitive to apoptosis induced by these agents than WT cells. Previous studies have also shown that expression of certain genes involved in cell cycle regulation is different between WT and Y8 cells. Recent evidence suggests that a serine/threonine kinase is involved in the divergent cellular responses of these cells. In the present study, the effects of roscovitine, a cyclin-dependent kinase inhibitor, were examined on the WT and Y8 cells. The WT cells blocked in G2/M, whereas Y8 cells became apoptotic. Apoptosis induced by roscovitine in the Y8 cells was mediated by a caspase-3-like activity. NF kappa B was activated to a much greater extent by roscovitine in the WT cells than in Y8 cells. The data also indicate that cyclin B1/cdc2 plays a role in the divergent p53-independent G2/M block and apoptotic responses of the WT and Y8 cells, respectively. Several key factors such as cathepsin B, caspase-1, release of cytochrome c into the cytosol, TNF-alpha signaling, FasL/Fas signaling, c-myc overexpression, and E2F-1 overexpression and induction were shown not to be involved in the apoptotic pathway(s) in the Y8 cells.
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PMID:Enhanced roscovitine-induced apoptosis is mediated by a caspase-3-like activity in deoxyadenosine-resistant mouse leukemia L1210 cells. 1113 34

Cardiac hypertrophy is a complex process involving the coordinated actions of many genes. In a high throughput screen designed to identify transcripts that are actively translated during cardiac hypertrophy, we identified a number of genes with established links to hypertrophy, including those coding for Sp3, c-Jun, annexin II, cathepsin B, and HB-EGF, thus showing the general utility of the screen. Focusing on a candidate transcript that has not been previously linked to hypertrophy, we found that protein levels of the tumor suppressor PTEN (phosphatase and tensin homologue on chromosome ten) were increased in the absence of increased messenger RNA levels. Increased PTEN expression by recombinant adenovirus in cultured neonatal rat primary cardiomyocytes caused cardiomyocyte apoptosis as evidenced by increased caspase-3 activity and cleaved poly(A)DP-ribose polymerase. Expression of PTEN was also able to block growth factor signaling through the phosphatidylinositol 3,4,5-triphosphate pathway. Surprisingly, expression of a catalytically inactive PTEN mutant led to cardiomyocyte hypertrophy, with increased protein synthesis, cell surface area, and atrial natriuretic factor expression. This hypertrophy was accompanied by an increase in Akt activity and improved cell viability in culture.
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PMID:The tumor suppressor gene PTEN can regulate cardiac hypertrophy and survival. 1144 56

In the last decade, the molecular mechanisms of apoptosis, a major type of active cell death (type I cell death) have largely been clarified in mammalian cells. Particularly, the caspase family of proteinases has been shown to play crucial roles in the execution of apoptosis. Differing from apoptosis, type II cell death is known to be associated with autophagosomes/autolysosomes and appear in the developing nervous system (CLARKE, 1990). We have previously shown that delayed neuronal death occurring in the CA1 pyramidal layer of the gerbil hippocampus after brief forebrain ischemia is apoptotic in nature and autophagosomes/autolysosomes abundantly appear in the neurons before DNA fragmentation. To further understand the roles of autophagosomes/autolysosomes in active cell death, we examined the apoptosis of PC12 cells using morphological and biochemical techniques. PC12 cells are known to undergo apoptosis when cultured in the absence of serum. In such an environment, the mitochondrial pathway of apoptosis is activated; cytochrome c is released from mitochondria, and caspase-9/caspase-3 are activated. We have first examined morphological features of PC12 cells during the apoptotic process following serum deprivation, and found that autophagy is induced from the early stage of the process in the cells before typical nuclear changes. When autophagy is inhibited in the cells by 3-methyladenine, an autophagy inhibitor, they are largely protected from apoptosis. In relation to the induction of autophagy in PC12 cells following serum deprivation, immunoreactivity, protein amounts, and the proteolytic activity of lysosomal proteinases, particularly cathepsins B and D, are all greatly altered; those of cathepsin B drastically decrease in the cells from the early stage of serum-deprived cultures, whereas those of cathepsin D increase. Moreover, PC12 cells overexpressing cathepsin D undergo apoptosis more rapidly in serum-deprived cultures than wild-type cells, whereas those overexpressing cathepsin B increase the viability. These lines of evidence suggest that autophagy is involved in PC12 cell death following serum deprivation, this type of cell death being regulated by lysosomal proteinases, cathepsins B and D, downstream autophagy.
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PMID:Autophagic cell death and its execution by lysosomal cathepsins. 1157 20

TWEAK, a recently identified member of the TNF family, is expressed on IFN-gamma-stimulated monocytes and induces cell death in certain tumor cell lines. In this study, we characterized the TWEAK-induced cell death in several tumor cell lines that exhibited distinct features. Although the TWEAK-induced cell death in Kym-1 cells was indirectly mediated by TNF-alpha and was inhibited by cycloheximide, the TWEAK-induced cell death in HSC3 cells or IFN-gamma-treated HT-29 cells was not inhibited by anti-TNF-alpha mAb or cycloheximide, suggesting a direct triggering of cell death via TWEAK receptor in the latter cell lines. The TWEAK-induced apoptosis in HSC3 cells and IFN-gamma-treated HT-29 cells was associated with caspase-8 and caspase-3 activation. Although a pan-caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone, inhibited the TWEAK-induced cell death in HSC3 cells, it rather sensitized HT-29 cells to TWEAK-induced cell death by necrosis. This necrosis was abrogated by lysosomal proteinase inhibitors, particularly a cathepsin B inhibitor, [L-3-trans-(propylcarbamoyl)oxirane-2-carbonyl]-L-isoleucyl-L-proline methyl ester. During the process of TWEAK-induced necrosis, cathepsin B was released from lysosome to cytosol. Although DR3 has been reported to be a receptor for TWEAK, all TWEAK-sensitive tumor cell lines used in this study did not express DR3 at either protein or mRNA level, but did bind CD8-TWEAK specifically. These results indicated that TWEAK could induce multiple pathways of cell death, including both caspase-dependent apoptosis and cathepsin B-dependent necrosis, in a cell type-specific manner via TWEAK receptor(s) distinct from DR3.
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PMID:Multiple pathways of TWEAK-induced cell death. 1177 67


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