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)

Members of the ICE/CED-3 protease family appear to play an essential role in programmed cell death process. In this paper the chromosomal localization of the human genes CPP32, Mch2, Mch3 and Ich-1 is reported, obtained by Radiation Hybrid Mapping. CPP32 was assigned to chromosome 4q33-q35.1, Mch2 to chromosome 4q25-q26, Mch3 to chromosome 10q25.1-q25.2 and Ich-1 to chromosome 7q35. Ich-1 was found to map very close to the marker WI-9353. The possible overlapping of the two independent locus assignments is considered. The genomic distribution of these genes is discussed, with particular reference to the co-location with some human genetic diseases all characterized by autosomal dominant inheritance and by similar malformative features.
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PMID:Chromosomal localization of the human genes, CPP32, Mch2, Mch3, and Ich-1, involved in cellular apoptosis. 878 Jul 21

A new member of the tumor necrosis factor (TNF) cytokine family, designated Apo-2 ligand (Apo-21) [1] or TRAIL [2], has been shown recently to induce apoptosis in various tumor cell lines; however, its biological role is unknown. Here, we show that Apo-21, activated apoptosis in T-cell-enriched cultures of peripheral blood lymphocytes stimulated by interleukin-2 (IL-2), but not in unstimulated cells. This finding suggests that, like Fas/Apo-1 ligand and TNF [3-5], Apo-2L may play a role in regulating post-stimulation apoptosis of mature lymphocytes. Studies on the mechanism of Apo-2L action demonstrated marked membrane blebbing, a hallmark of apoptosis, within a few minutes of the addition of Apo-2L to tumor cells. Ectopic expression of a dominant negative mutant of FADD, a cytoplasmic protein that mediates death signalling by Fas/Apo-1 and by TNF receptor type 1 (TNFR1) [6-9], inhibited the induction of apoptosis by anti-Fas/Apo-1 antibody, but had little effect on Apo-2L function. In contrast, expression of CrmA, a cowpox virus-derived inhibitor of the Ced-2-like proteases ICE [10] and CPP32/Yama [11,12], blocked the induction of apoptosis by either Apo-2L or anti-Fas/Apo-1 antibody. These results suggest that Apo-2L activates a rapid, FADD-independent pathway to trigger a cell-death programme that requires the function of cysteine proteases such as ICE or CPP32/Yama.
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PMID:Activation of apoptosis by Apo-2 ligand is independent of FADD but blocked by CrmA. 879 1

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

We demonstrate that the catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs) is specifically, proteolytically cleaved in HL-60 cells treated with staurosporine (STS), a potent inducer of apoptosis. The proteolysis of DNA-PKcs correlated with or preceded apoptotic chromosomal DNA degradation. Cell-free extracts prepared from STS-treated HL-60 cells recapitulated the proteolysis of DNA-PKcs in an in vitro assay using purified DNA-PK as the substrate. Western blot analyses of the apoptotic cell extract showed that the 32-kDa precursor of CPP32 is expressed in HL-60 cells and processed following STS treatment. In addition, whereas the DNA-PKcs protease activity was not inhibitable by many conventional protease inhibitors, it was inhibitable by a highly selective peptide-derived inhibitor of CPP32. These data strongly suggest that CPP32, or a CPP32-like protease, is responsible for DNA-PKcs proteolysis. Finally, our results demonstrated that the cleavage of DNA-PKcs in vitro proceeded in the presence of Bcl-2, indicating that the function provided by Bcl-2 lies upstream the proteolysis of DNA-PKcs.
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PMID:DNA-dependent protein kinase is a target for a CPP32-like apoptotic protease. 879 86

DNA-dependent protein kinase (DNA-PK) is composed of a 460-kDa catalytic component (p460) and a DNA-binding component Ku protein. Immunoblot analysis after treatment of Jurkat cells with anti-Fas antibody demonstrated the cleavage of p460 concomitantly with an increase in CPP32/Yama/apopain activity. Recombinant CPP32/Yama/apopain specifically cleaved p460 in the DNA-PK preparation that had been purified from Raji cells into 230- and 160-kDa polypeptides, the latter of which was detected in anti-Fas-treated Jurkat cells. The regulatory component Ku protein was not significantly affected by CPP32/Yama/apopain. DNA-PK activity was decreased with the disappearance of p460 in the incubation of DNA-PK with CPP32/Yama/apopain. These results suggest that the catalytic component of DNA-PK is one of the target proteins for CPP32/Yama/apopain in Fas-mediated apoptosis.
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PMID:CPP32/Yama/apopain cleaves the catalytic component of DNA-dependent protein kinase in the holoenzyme. 880 12

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

We studied the role of proteases in apoptosis using a cell-free system prepared from a human leukemia cell line. HL60 cells are p53 null and extremely sensitive to a variety of apoptotic stimuli including DNA damage induced by the topoisomerase I inhibitor, camptothecin. We measured DNA fragmentation induced in isolated nuclei by cytosolic extracts using a filter elution assay. Cytosol from camptothecin-treated HL60 cells induced internucleosomal DNA fragmentation in nuclei from untreated cells. This fragmentation was suppressed by serine protease inhibitors. Serine proteases (trypsin, endoproteinase Glu-C, chymotrypsin A, and proteinase K) and papain by themselves induced DNA fragmentation in naive nuclei. This effect was enhanced in the presence of cytosol from untreated cells. Cysteine protease inhibitors (E-64, leupeptin, Ac-YVAD-CHO [ICE inhibitor]) did not affect camptothecin-induced DNA fragmentation. The apopain/Yama inhibitor, Ac-DEVD-CHO, and the proteasome inhibitor, MG-132, were also inactive both in the cell-free system and in whole cells. Interleukin-1 beta converting enzyme (ICE) or human immunodeficiency virus protease failed to induce DNA fragmentation in naive nuclei. Together, these results suggest that DNA damage activates serine protease(s) which in turn activate(s) nuclear endonuclease(s) during apoptosis in HL60 cells.
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PMID:DNA fragmentation induced by protease activation in p53-null human leukemia HL60 cells undergoing apoptosis following treatment with the topoisomerase I inhibitor camptothecin: cell-free system studies. 880 33

Apoptosis may involve a specialized proteolytic cascade catalyzed by interleukin-1beta-converting enzyme-like proteases. We have recently identified three new members of this family (CPP32, MCH2, MCH3) and shown that they play an important role in promoting cell death. Here we report the chromosomal mapping of CPP32 to 4q34, MCH2 to 4q25, and MCH3 to 10q25.
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PMID:Chromosomal mapping of cell death proteases CPP32, MCH2, and MCH3. 881 67

The response of human myeloid leukemia cells to treatment with 1-beta-arabinofuranosylcytosine (ara-C) includes the induction of apoptosis. Ara-C induced apoptosis is associated with proteolytic cleavage of poly(ADP-ribose) polymerase (PARP) and protein kinase C (PKC) delta. However, the signals involved in this response are unknown. The present studies show that ara-C treatment of U-937 cells is associated with induction of a protease activity that cleaves the tetrapeptides Ac-DEVD-pNA and Ac-DMOD-pNA found at the cleavage sites of PARP and PKC delta, respectively. The ara-C-induced protease activity was sensitive to overexpression of the anti-apoptotic protein Bcl-xL and the baculovirus protein p35. By contrast, overexpression of the cowpox virus protein CrmA blocked apoptosis induced by engagement of the Fas receptor but not that induced by ara-C. CrmA overexpression also had no detectable effect on ara-C-induced cleavage of PKC delta. The results further show that ara-C induces activation of the CPP32 protease by a CrmA-insensitive and p35-sensitive mechanism. Similar results were obtained with cisplatinum, etoposide, and camptothecin. These findings indicate that ara-C and other DNA-damaging agents activate a CrmA-insensitive apoptotic pathway involving CPP32 and that these signals differ from those associated with apoptosis induced by the Fas receptor.
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PMID:Activation of the CPP32 protease in apoptosis induced by 1-beta-D-arabinofuranosylcytosine and other DNA-damaging agents. 882 10

Previously we have shown that oxidized low density lipoprotein (Ox-LDL) induced apoptosis in vascular smooth muscle cells (VSMCs) and that this apoptosis contributed to oxysterol, 7-ketocholesterol. The aim in this present study was to identify the mechanism by which oxysterols induced apoptosis in VSMCs. We show that both 7-ketocholesterol and 25-hydroxycholesterol induced apoptosis, followed by a rapid decrease in bcl-2 protein in the cells. CPP32/Yamma inhibitor prevented apoptosis induced by 7-ketocholesterol and 25-hydroxycholesterol in VSMCs, whereas the exogenous cholesterol, which itself did not have any apoptotic activity, inhibited 25-hydroxycholesterol induced apoptosis but the 7-ketocholesterol-induced apoptosis was not affected. These results suggest that 25-hydroxycholesterol induced-apoptosis occurs by a different mechanism than 7-ketocholesterol induced-apoptosis.
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PMID:Oxysterols induced apoptosis in cultured smooth muscle cells through CPP32 protease activation and bcl-2 protein downregulation. 883 13


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