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)

A cytoplasmic protease was partially purified from Escherichia coli; its sedimentation coefficient was found to be 5.3 S. This enzyme (which we call protease A) is not a serine protease and cysteine is not required for its activity; it is only active in the presence of divalent ions which are strongly bound to it. After inactivation of protease A by incubation at 50 degrees C in the presence of 1 mM EDTA, the enzyme is reactived by Mg2+, Mn2+ or Ca2+. We have tried most of the usual esters as substrates and found that none was hydrolyzed by the enzyme which induces a highly restricted specificity.
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PMID:Properties of a cytoplasmic proteolytic enzyme from Escherichia coli. 80 69

Genetic analyses of Caenorhabditis elegans has identified three genes that function in the regulation of nematode cell death. Mammalian homologs of two of these genes, ced-9 and ced-3, have been identified and comprise proteins belonging to the Bcl-2 and ICE families, respectively. To date, it is unclear where the negative regulators, ced-9 and bcl-2, function relative to the death effectors, ced-3 and the mammalian ced-3 homologs, respectively. Here, the molecular order of the cell death pathway is defined. Our results establish that Bcl-2 and Bcl-xL function upstream of two members of the ICE/CED-3 family of cysteine proteases, Yama (CPP32/apopain) and ICE-LAP3 (Mch3).
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PMID:Molecular ordering of the cell death pathway. Bcl-2 and Bcl-xL function upstream of the CED-3-like apoptotic proteases. 861 12

Apoptosis (programmed cell death) is a fundamental process for normal development of multicellular organisms, and is involved in the regulation of the immune system, normal morphogenesis, and maintenance of homeostasis, ICE/CED-3 family cysteine proteases have been implicated directly in apoptosis, but relatively few of the substrates through which their action is mediated have been identified. Here we report that D4-GDI, an abundant hematopoietic cell GDP dissociation inhibitor for the Ras-related Rho family GTPases, is a substrate of the apoptosis protease CPP32/Yama/Apopain. D4-GDI was rapidly truncated to a 23-kDa fragment in Jurkat cells with kinetics that parallel the onset of apoptosis following Fas cross-linking with agonistic antibody or treatment with staurosporine. Fas- and staurosporine-induced apoptosis as well as cleavage of D4-GDI were inhibited by the ICE inhibitor, YVAD-cmk. D4-GDI was cleaved in vitro by recombinant CPP32 expressed in Escherichia coli to form a 23-kDa fragment. The CPP32-mediated cleavage of D4-GDI was completely inhibited by 1 microM DEVD-CHO, a reported selective inhibitor of CPP32. In contrast, the ICE-selective inhibitors, YVAD-CHO or YVAD-cmk, did not inhibit CPP32-mediated D4-GDI cleavage at concentrations up to 50 microM. N-terminal sequencing of the 23-kDa D4-GDI fragment demonstrated that D4-GDI was cleaved between Asp19 and Ser20 of the poly(ADP-ribose) polymerase-like cleavage sequence DELD19S. These data suggest that regulation by D4-GDI of Rho family GTPases may be disrupted during apoptosis by CPP32-mediated cleavage of the GDI protein.
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PMID:D4-GDI, a substrate of CPP32, is proteolyzed during Fas-induced apoptosis. 862 69

The Caenorhabditis elegans cell death gene, ced-3, encodes one of the two proteins required for apoptosis in this organism. The primary sequence similarities between Ced-3 and the mammalian interleukin-1beta converting enzyme (ICE) suggest that these two proteins may have functionally similar active sites and that Ced-3 may function as a cysteine protease. Here we report that in vitro transcribed and translated Ced-3 protein (p56) underwent rapid processing to smaller fragments. Replacement of the predicted active site cysteine of Ced-3 with serine (C364S) prevented the generation of smaller proteolytic fragments, suggesting that the processing might be an autocatalytic process. Peptide aldehydes with aspartic acid at the P1 position blocked Ced-3 autocatalysis. Furthermore, the protease inhibition profile of Ced-3 was similar to the profile reported for ICE. These functional data demonstrate that Ced-3 is an Asp-dependent cysteine protease with substrate specificity similar to that of ICE. Aurintricarboxylic acid, an inhibitor of apoptosis in mammalian cells, blocked Ced-3 autocatalytic activity, suggesting that an aurintricarboxylic acid-sensitive Ced-3/ICE-related protease might be involved in the apoptosis pathway(s) in mammalian cells.
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PMID:Protease activity of in vitro transcribed and translated Caenorhabditis elegans cell death gene (ced-3) product. 863 56

The Bcl-2 family and the ICE family of cysteine proteases play important roles in regulating cell death. We show here that induction of cell death by a Ca2+ ionophore or hypoxia results in increased levels and activity of active ICE(-like) proteases and the subsequent activation of CPP32/Yama(-like) proteases, and that inhibition of these protease activities reduces the extent of cell death. Overexpression of the anti-apoptotic proteins Bcl-2 or Bcl-xL inhibits the cell death and the activation of ICE(-like) and CPP32/Yama(-like) proteases, indicating that Bcl-2 and Bcl-xL act upstream of these proteases. We also show that specific inhibition of ICE(-like) proteases in vivo prevents activation of CPP32/Yama(-like) proteases, whereas inhibition of CPP32/Yama(-like) proteases does not prevent activation of ICE(-like) proteases, suggesting the existence of a protease cascade in vivo that requires ICE(-like) proteases for activation of CPP32/Yama(-like) proteases. Induction of necrotic cell death by KCN also induces activation of ICE(-like) proteases but not of CPP32/Yama(-like) proteases, and Bcl-2 and Bcl-xL inhibit the activation and the cell death, suggesting that the functional site of Bcl-2 and Bcl-xL is also upstream of ICE(-like) proteases in at least some forms of necrosis.
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PMID:Bcl-2 expression prevents activation of the ICE protease cascade. 864 64

The human proto-oncogene bcl-2 and its Caenorhabditis elegans homologue ced-9 inhibit programmed cell death. In contrast, members of the human interleukin-1beta converting enzyme (ICE) family of cysteine proteases and their C. elegans homologue CED-3 promote the death program. Genetic experiments in C. elegans have shown that ced-9 is formally a negative regulator of ced-3 function, but neither those studies nor others have determined whether CED-9 or Bcl-2 proteins act biochemically upstream or downstream of CED-3/ICE proteases. CPP32, like all known members of the CED-3/ICE family, is synthesized as a proenzyme that is subsequently processed into an active protease with specificity for cleavage at Asp-X peptide bonds. In this report, we demonstrate that the CPP32 proenzyme is proteolytically processed and activated in Jurkat cells induced to die by Fas ligation. CPP32 activation is blocked by cell-permeable inhibitors of aspartate-directed, cysteine proteases, suggesting that pro-CPP32 is cleaved by active CPP32 or by other ICE family members. Heterologous expression of Bcl-2 in Jurkat cells prevents Fas-induced cell death as well as proteolytic processing and activation of CPP32. Thus, Bcl-2 acts at or upstream of the CPP32 activation step to inhibit apoptosis induced by Fas stimulation.
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PMID:Fas-induced activation of the cell death-related protease CPP32 Is inhibited by Bcl-2 and by ICE family protease inhibitors. 866 39

Phylogenetic analysis of the CED-3/ICE family of cysteine proteases suggests the existence of a subfamily most related to the Caenorhabditis elegans death gene ced-3 and includes Yama (CPP32, apopain), LAP3 (Mch3, CMH1), and Mch2. Here, we show that Mch2 is processed from its zymogen form to a proteolytically active dimeric species during execution of the apoptotic program and by the cytotoxic T cell death protease granzyme B. Additionally, like Yama and LAP3, Mch2 functions downstream of the death inhibitors Bcl-2, Bcl-xL, and CrmA. Importantly, Mch2, but not Yama or LAP3, is capable of cleaving lamin A to its signature apoptotic fragment, indicating that Mch2 is an apoptotic laminase.
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PMID:The CED-3/ICE-like protease Mch2 is activated during apoptosis and cleaves the death substrate lamin A. 866 80

To identify CAP3 and CAP4, components of the CD95 (Fas/APO-1) death-inducing signaling complex, we utilized nano-electrospray tandem mass spectrometry, a recently developed technique to sequence femtomole quantities of polyacrylamide gel-separated proteins. Interestingly, CAP4 encodes a novel 55 kDa protein, designated FLICE, which has homology to both FADD and the ICE/CED-3 family of cysteine proteases. FLICE binds to the death effector domain of FADD and upon overexpression induces apoptosis that is blocked by the ICE family inhibitors, CrmA and z-VAD-fmk. CAP3 was identified as the FLICE prodomain which likely remains bound to the receptor after proteolytic activation. Taken together, this is unique biochemical evidence to link a death receptor physically to the proapoptotic proteases of the ICE/CED-3 family.
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PMID:FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death--inducing signaling complex. 868 77

Apoptosis is executed by cysteine proteases belonging to the CED-3/ICE family, which, unlike other mammalian cysteine proteases, cleave their substrates following aspartate residues. Proteases belonging to this family exist in the cytosol as zymogens that require accurate processing at internal aspartate residues to generate the two-chain active enzymes. As such, CED-3/ICE family members are capable of activating each other in a manner analogous to the protease zymogens of the coagulation or complement cascades. At present, it is unknown whether such mutual processing exists in vivo, and if so whether it is sequential, implying an order to the death pathway. Using a cell-free apoptosis system, recombinant ICE proteases and both biochemical and morphological criteria, we demonstrate an ordering of the mammalian ICEs that are most related to the Caenorhabditis elegans death protease CED-3.
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PMID:Molecular ordering of apoptotic mammalian CED-3/ICE-like proteases. 870 58

Cytotoxic T lymphocytes (CTLs) are able to kill target cells bearing foreign antigen through two distinct mechanisms: granule- and Fas-mediated cytotoxicity. The exact events involved in the induction of target cell apoptosis remain elusive, but research indicates a role for members of the interleukin-1beta converting enzyme (ICE)/Ced-3 family of cysteine proteases. The exact nature of the protease(s) involved is yet to be determined. Here we use activity assays and peptide inhibitors of ICE/Ced-3 proteases to study their role in Fas-mediated killing. We find that while certain inhibitors block DNA fragmentation and chromium release, others do not. Most notably, potent inhibitors of CPP32 and ICE could not inhibit DNA fragmentation during all cases of Fas-mediated cytotoxicity although an "ICE" inhibitor could suppress 51Cr release. Additionally, we find that CPP32 is not cleaved in all target cells during Fas killing. Although ICE activity (as measured by a fluorogenic substrate) is present in cell lysates from anti-Fas-treated cells, we found no pro-IL-1beta-cleaving activity in these lysates. Taken together, our results suggest that an alternate pathway to DNA fragmentation exists, which does not involve CPP32 activity, and that CPP32 and ICE activities are not essential to Fas-mediated killing.
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PMID:An interleukin-1beta converting enzyme-like protease is a key component of Fas-mediated apoptosis. 870 62


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