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:3.4.22.36 (caspase-1)
6,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sympathetic neurons undergo programmed cell death (PCD) upon deprivation of nerve growth factor (NGF). PCD of neurons is blocked by inhibitors of the interleukin-1beta converting enzyme (ICE)/Ced-3-like cysteine protease, indicating involvement of this class of proteases in the cell death programme. Here we demonstrate that the proteolytic activities of the proteasome are also essential in PCD of neurons. Nanomolar concentrations of several proteasome inhibitors, including the highly selective inhibitor lactacystin, not only prolonged survival of NGF-deprived neurons but also prevented processing of poly(ADP-ribose) polymerase which is known to be cleaved by an ICE/Ced-3 family member during PCD. These results demonstrate that the proteasome is a key regulator of neuronal PCD and that, within this process, it is involved upstream of proteases of the ICE/Ced-3 family. This order of events was confirmed in macrophages where lactacystin inhibited the proteolytic activation of precursor ICE and the subsequent generation of active interleukin-1beta.
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PMID:Involvement of the proteasome in the programmed cell death of NGF-deprived sympathetic neurons. 867 Aug 89

The ICE/CED-3 family of proteases has been implicated in playing a fundamental role in programmed cell death. Bcl-2 protein represses a number of apoptotic death programs, but the biochemical mechanism of its action is not known. We investigated the activation of ICE/CED-3 proteases induced by three apoptotic stimuli (staurosporine, ceramide, and serum withdrawal) in the neuronal cell line GT1-7 and in cells overexpressing Bcl-2. Rapid activation of a 17 kDa subunit of an activated member of the ICE/CED-3 family is demonstrated by affinity-labeling GT1-7 extracts from apoptotic controls cells with a biotinylated ICE/CED-3 inhibitor. This activation corresponds to an increased ICE/CED-3-like protease activity in extracts measured by a fluorogenic substrate assay. In a cell-free system, these extracts induce apoptotic morphological changes in intact nuclei. All three activities are readily inhibited by treatment of control extracts with ICE/CED-3-like protease inhibitors. Overexpressed Bcl-2 inhibits the activation of the 17 kDa protein, the ICE/CED-3-like protease activity in the fluorogenic assay, and the induction of apoptotic morphological changes in HeLa nuclei in the cell-free system, similar to results obtained with ICE/CED-3 protease inhibitors. At the mRNA level, overexpression of Bcl-2 did not alter expression of five members of the ICE/CED-3 family: CPP32, ICE, Mch 2, Nedd 2, and TX. Overexpression of Bcl-2 prevented the apoptosis-induced processing of pro-Nedd 2 to the cleaved form. These data suggest that Bcl-2 participates upstream from the function of ICE/CED-3 proteases and may inhibit apoptosis by preventing the post-translational activation of ICE/CED-3 proteases.
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PMID:Bcl-2 expression in neural cells blocks activation of ICE/CED-3 family proteases during apoptosis. 879 21

Cytotoxic T lymphocytes (CTLs) and natural killers (NK) cells provide immune surveillance against viruses and neoplasms, and play a central role in the pathogenesis of autoimmune disease, AIDS and graft rejection. Thus, it is important to understand the precise molecular mechanism(s) whereby cytotoxic lymphocytes destroy susceptible target cells. Granule-mediated cytotoxicity requires a combination of both perforin and granzyme B. Perforin polymerizes to form transmembrane channels and presumably allows granzyme B access to target cell substrates, which until recently, were unknown. One clue to the identity of the physiological substrate(s) activated by granzyme B comes from its unusual specificity for cleaving synthetic substrates after aspartate residues. Members of the ICE/CED-3 family of cysteine proteases are prime candidates as they are important apoptotic effectors and are expressed as zymogens, which can be processed to form active heterodimeric enzymes after cleavage at specific aspartate residues. Previous studies have shown that granzyme B proteolytically activates the cell death effector Yama/CPP32/apopain (referred to here as Yama). Here we report that granzyme B also activates ICE-LAP3/Mch3/CMH-1 (referred to here as ICE-LAP3), which, along with Yama and Mch2, forms a subset of the ICE/CED-3 family of cysteine proteases most closely related to the Caenorhabditis elegans cell death gene, CED-3. Importantly, Jurkat T cells incubated with granzyme B and a sublytic concentration of perforin undergo apoptosis, which is preceded by the activation of endogenous ICE-LAP3. Thus, we propose that granzyme B mediates apoptosis by directly engaging the target cell's death effector machinery, which is probably composed of an arsenal of intracellular, CED-3-like cysteine proteases.
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PMID:Cytotoxic T-cell-derived granzyme B activates the apoptotic protease ICE-LAP3. 880 7

The Fas/APO-1-receptor associated cysteine protease Mch5 (MACH/FLICE) is believed to be the enzyme responsible for activating a protease cascade after Fas-receptor ligation, leading to cell death. The Fas-apoptotic pathway is potently inhibited by the cowpox serpin CrmA, suggesting that Mch5 could be the target of this serpin. Bacterial expression of proMch5 generated a mature enzyme composed of two subunits, which are derived from the pre-cursor proenzyme by processing at Asp-227, Asp-233, Asp-391, and Asp-401. We demonstrate that recombinant Mch5 is able to process/activate all known ICE/Ced-3-like cysteine proteases and is potently inhibited by CrmA. This contrasts with the observation that Mch4, the second FADD-related cysteine protease that is also able to process/activate all known ICE/Ced-3-like cysteine proteases, is poorly inhibited by CrmA. These data suggest that Mch5 is the most upstream protease that receives the activation signal from the Fas-receptor to initiate the apoptotic protease cascade that leads to activation of ICE-like proteases (TX, ICE, and ICE-relIII), Ced-3-like proteases (CPP32, Mch2, Mch3, Mch4, and Mch6), and the ICH-1 protease. On the other hand, Mch4 could be a second upstream protease that is responsible for activation of the same protease cascade in CrmA-insensitive apoptotic pathways.
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PMID:Molecular ordering of the Fas-apoptotic pathway: the Fas/APO-1 protease Mch5 is a CrmA-inhibitable protease that activates multiple Ced-3/ICE-like cysteine proteases. 896 78

Upon treatment with various anticancer drugs, myeloid leukemia U937 cells undergo apoptosis. In this study, we found that either etoposide (VP-16) or camptothecin (CPT) activated c-Jun N-terminal kinase 1/stress-activated protein kinase (JNK1/SAPK), transient c-jun expression, and ICE (interleukin-1beta converting enzyme)/CED-3-like proteases in U937 cells. Phorbol ester-resistant U937 variant, UT16 cells, displayed a decreased susceptibility to apoptosis induced by these drugs. The drugs did not cause JNK1 activation, c-jun expression, nor activation of ICE/CED-3-like proteases in UT16 cells. As reported previously, benzyloxycarbonyl-Asp-CH2OC(O)-2,6-dichlorobenzene (Z-Asp), a preferential inhibitor of ICE/CED-3-like proteases, blocked the apoptosis of U937 cells. Interestingly, however, Z-Asp did not inhibit JNK1 activation in either VP-16- or CPT-treated U937 cells. The JNK1 antisense oligonucleotides diminished protein expression of JNK1 and inhibited drug-induced apoptosis of U937 cells, whereas sense control oligonucleotides did not. Consistent with this observation, the antisense oligonucleotide-treated cells did not respond to VP-16 or CPT with Z-Asp-sensitive proteases. These results indicate that JNK1 triggers the DNA damaging drug-induced apoptosis of U937 cells by activating Z-Asp-sensitive ICE/CED-3-like proteases.
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PMID:c-Jun NH2-terminal kinase-mediated activation of interleukin-1beta converting enzyme/CED-3-like protease during anticancer drug-induced apoptosis. 902 Jan 92

Anticancer agents have been shown to trigger apoptosis in chemosensitive tumors such as neuroblastomas. We previously identified activation of the CD95 system as one of the key mechanisms for doxorubicin-induced apoptosis in leukemic T cells. Here, we report that therapeutic concentrations of doxorubicin, cisplatinum, and VP-16 led to induction of CD95 receptor and CD95 ligand (CD95-L) that mediated cell death in chemosensitive neuroblastoma cells. Using F(ab')2 anti-CD95 antibody fragments to interfere with CD95-L-receptor interaction markedly reduced apoptosis induced by those drugs in vitro. Cyclosporin A inhibited induction of CD95 mRNA and CD95-L mRNA and blocked drug-mediated apoptosis. Drug-induced apoptosis involved activation of caspases (interleukin 1beta-converting enzyme/Ced-3-like proteases) and processing of the prototype caspase substrate PARP and was completely blocked by benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, a peptide inhibitor of caspases. In addition, neuroblastoma cells that were resistant to CD95-triggered apoptosis also displayed cross-resistance to chemotherapeutic agents. These data provide new clues for understanding the molecular requirements for drug-induced apoptosis in chemosensitive neuroblastoma cells by demonstrating that cell death was mediated via the CD95-L-receptor system and may open new avenues for targeting drug resistance of neuroblastoma.
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PMID:The CD95 (APO-1/Fas) system mediates drug-induced apoptosis in neuroblastoma cells. 928 94

Betulinic acid (BA), a melanoma-specific cytotoxic agent, induced apoptosis in neuroectodermal tumors, such as neuroblastoma, medulloblastoma, and Ewing's sarcoma, representing the most common solid tumors of childhood. BA triggered an apoptosis pathway different from the one previously identified for standard chemotherapeutic drugs. BA-induced apoptosis was independent of CD95-ligand/receptor interaction and accumulation of wild-type p53 protein, but it critically depended on activation of caspases (interleukin 1beta-converting enzyme/Ced-3-like proteases). FLICE/MACH (caspase-8), considered to be an upstream protease in the caspase cascade, and the downstream caspase CPP32/YAMA/Apopain (caspase-3) were activated, resulting in cleavage of the prototype substrate of caspases PARP. The broad-spectrum peptide inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone, which blocked cleavage of FLICE and PARP, also completely abrogated BA-triggered apoptosis. Cleavage of caspases was preceded by disturbance of mitochondrial membrane potential and by generation of reactive oxygen species. Overexpression of Bcl-2 and Bcl-XL conferred resistance to BA at the level of mitochondrial dysfunction, protease activation, and nuclear fragmentation. This suggested that mitochondrial alterations were involved in BA-induced activation of caspases. Furthermore, Bax and Bcl-xs, two death-promoting proteins of the Bcl-2 family, were up-regulated following BA treatment. Most importantly, neuroblastoma cells resistant to CD95- and doxorubicin-mediated apoptosis were sensitive to treatment with BA, suggesting that BA may bypass some forms of drug resistance. Because BA exhibited significant antitumor activity on patients' derived neuroblastoma cells ex vivo, BA may be a promising new agent for the treatment of neuroectodermal tumors in vivo.
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PMID:Betulinic acid triggers CD95 (APO-1/Fas)- and p53-independent apoptosis via activation of caspases in neuroectodermal tumors. 986 49

The ability of cryptophycin 1, a new potent cytotoxic antimicrotubule agent, to initiate apoptosis was studied. Treatment of cells with cryptophycin 1 (50 pM) rapidly caused morphological changes consistent with the induction of apoptosis. DNA strand breakage and fragmentation of the DNA into oligonucleosome-sized fragments was observed, and this coincided with the loss of cellular DNA. Activation of the cysteine protease CPP32 (caspase 3, YAMA, apopain), a member of the ICE/CED-3-like protease family of apoptosis effectors, was consistent with the execution of cell death by a coordinated sequence of events. Low concentrations of cryptophycin 1 caused mitotic arrest with the formation of abnormal mitotic spindles without affecting interphase microtubule structures. Unlike other microtubule active agents, cryptophycin-induced mitotic arrest persisted for only a brief period before the onset of apoptosis. There was no evidence of release from G2/M cell cycle arrest. Our results show that low concentrations of cryptophycin 1 (50 pM) initiated cell death consistent with apoptosis. These data suggest that the cytotoxic effects of cryptophycin 1 are due in part to its ability to initiate apoptosis rapidly.
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PMID:Induction of apoptosis by cryptophycin 1, a new antimicrotubule agent. 935 93

Treatment of U-937 promonocytic cells with the DNA topoisomerase II inhibitor etoposide rapidly caused death by apoptosis, as determined by changes in chromatin structure, production of DNA breaks, nucleosome-sized DNA degradation, decrease in mitochondrial membrane potential and phosphatidyl serine translocation in the plasma membrane, and at the same time induced intracellular acidification. Both the execution of the apoptotic process and the intracellular acidification were reduced by the addition of forskolin plus theophylline or other cAMP increasing agents. These agents also attenuated the induction of apoptosis by camptothecin, heat-shock, cadmium chloride and X-radiation. Although etoposide slightly increased the production of reactive oxygen intermediates, this increase was not prevented by forskolin plus theophylline, and the addition of antioxidant agents failed to inhibit apoptosis. Etoposide caused a great increase in NF-(kappa)B binding activity, which was not prevented by forskolin plus theophylline, while AP-1 binding was little affected by the topoisomerase inhibitor. The treatments did not significantly alter the levels of Bcl-2 and Bax. By contrast, the expression of c-myc, which was very high in untreated U-937 cells and only partially inhibited by etoposide, was rapidly and almost totally abolished by the cAMP increasing agents. Finally, it was observed that etoposide caused a transient dephosphorylation of retinoblastoma (Rb), which was associated with cleavage of poly(ADP-ribose) polymerase (PARP). Both Rb dephosphorylation and PARP cleavage were inhibited by forskolin plus theophylline. The inhibition of Rb (type I) phosphatase and ICE/CED-3-like protease activities, and the abrogation of c-myc expression, are mechanisms which could explain the anti-apoptotic action of cAMP increasing agents in myeloid cells.
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PMID:cAMP increasing agents attenuate the generation of apoptosis by etoposide in promonocytic leukemia cells. 945 37

We have identified the CD95 system as a key mediator of chemotherapy-induced apoptosis in leukemia and neuroblastoma cells. Here, we report that sensitivity of various solid tumor cell lines for drug-induced cell death corresponds to activation of the CD95 system. Upon drug treatment, strong induction of CD95 ligand (CD95-L) and caspase activity were found in chemosensitive tumor cells (Hodgkin, Ewing's sarcoma, colon carcinoma and small cell lung carcinoma) but not in tumor cells which responded poorly to drug treatment (breast carcinoma and renal cell carcinoma). Blockade of CD95 using F(ab')2 anti-CD95 antibody fragments markedly reduced drug-induced apoptosis, suggesting that drug-triggered apoptosis depended on CD95-L/receptor interaction. Moreover, drug treatment induced CD95 expression, thereby increasing sensitivity for CD95-induced apoptosis. Drug-induced apoptosis critically depended on activation of caspases (ICE/Ced-3-like proteases) since the broad-spectrum inhibitor of caspases zVAD-fmk strongly reduced drug-mediated apoptosis. The prototype substrate of caspases, poly(ADP-ribose) polymerase, was cleaved upon drug treatment, suggesting that CD95-L triggered autocrine/paracrine death via activation of caspases. Our data suggest that chemosensitivity of solid tumor cells depends on intact apoptosis pathways involving activation of the CD95 system and processing of caspases. Our findings may have important implications for new treatment approaches to increase sensitivity and to overcome resistance of solid tumors.
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PMID:Chemosensitivity of solid tumor cells in vitro is related to activation of the CD95 system. 953 69


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