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)

The effector arm of the cell-death pathway is composed of cysteine proteases belonging to the ICE/CED-3 family. In metazoan cells these exist as inactive polypeptide precursors (zymogens), each composed of a prodomain, which is cleaved to activate the protease, and a large and small catalytic subunit. The coupling of these 'death' proteases to signalling pathways is probably mediated by adaptor molecules that contain protein-protein interaction motifs such as the death domain. Here we describe such an adaptor molecule, RAIDD, which has an unusual bipartite architecture comprising a carboxy-terminal death domain that binds to the homologous domain in RIP, a serine/threonine kinase component of the death pathway. The amino-terminal domain is surprisingly homologous with the sequence of the prodomain of two ICE/CED-3 family members, human ICH-1 (ref. 5) and Caenorhabditis elegans CED-3 (ref. 6). This similar region mediates the binding of RAIDD to ICH-1 and CED-3, serving as a direct link to the death proteases, indicating that the prodomain may, through homophilic interactions, determine the specificity of binding of ICE/CED-3 zymogens to regulatory adaptor molecules. Finally, alternations in the sequence of the N-terminal domain that are equivalent to inactivating mutations in the C. elegans ced-3 gene prevent homophilic binding, highlighting the potentially primordial nature of this interaction.
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PMID:RAIDD is a new 'death' adaptor molecule. 898 53

Apoptosis, a form of cellular suicide, involves the activation of CED-3-related cysteine proteases (caspases). The regulation of caspases by apoptotic signals and the precise mechanism by which they kill the cell remain unknown. In Drosophila, different death-inducing stimuli induce the expression of the apoptotic activator reaper. Cell killing by reaper and two genetically linked apoptotic activators, hid and grim, requires caspase activity. A Drosophila caspase, named Drosophila caspase-1 (DCP-1), was identified and found to be structurally and biochemically similar to Caenorhabditis elegans CED-3. Loss of zygotic DCP-1 function in Drosophila caused larval lethality and melanotic tumors, showing that this gene is essential for normal development.
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PMID:DCP-1, a Drosophila cell death protease essential for development. 899 99

Engagement of CD95 or tumor necrosis factor 1 receptor (TNFR-1) by ligand or agonist antibodies is capable of activating the cell death program, the effector arm of which is composed of mammalian interleukin-1beta converting enzyme (ICE)-like cysteine proteases (designated caspases) that are related to the Caenorhabditis elegans death gene, CED-3. Caspases, unlike other mammalian cysteine proteases, cleave their substrates following aspartate residues. Furthermore, proteases belonging to this family exist as zymogens that in turn require cleavage at internal aspartate residues to generate the two-subunit active enzyme. As such, family members are capable of activating each other. Remarkably, both CD95 and TNFR-1 death receptors initiate apoptosis by recruiting a novel ICE/CED-3 family member, designated FLICE/MACH, to the receptor signaling complex. Therefore, FLICE/MACH represents the apical triggering protease in the cascade. Consistent with this, recombinant FLICE was found capable of proteolytically activating downstream caspases. Furthermore, CrmA, a pox virus-encoded serpin that inhibits Fas and tumor necrosis factor-induced cell death attenuates the ability of FLICE to activate downstream caspases.
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PMID:FLICE induced apoptosis in a cell-free system. Cleavage of caspase zymogens. 900 41

Apoptosis occurs during development and tissue homeostasis, and under conditions of physical and chemical stress. During apoptosis, cells digest their DNA, decrease intracellular pH, shrink, exhibit protein phosphatase activity, and activate members of the ICE/CED-3 family of proteases. This protease activity is identified by cleavage of poly(ADP-ribose) polymerase (PARP). Phosphatase activity during apoptosis is observed as dephosphorylation of the retinoblastoma susceptibility protein (Rb). Serine/threonine phosphatase inhibitors can prevent dephosphorylation of Rb and apoptosis, suggesting that Rb dephosphorylation is an indication of a critical regulator of apoptosis. The experiments described here were designed to establish the temporal relationship between these events. Apoptosis was induced in human ML-1 cells by the topoisomerase inhibitor etoposide. An inhibitor of the ICE/CED-3 protease family, z-VAD-fluoromethylketone (FMK), showed concentration-dependent protection from PARP cleavage, intracellular acidification, DNA digestion, early changes in membrane permeability, and cell shrinkage, thereby placing all of these events downstream of the ICE/CED-3 protease action. However, z-VAD-FMK did not prevent the dephosphorylation of Rb, placing this change upstream of the protease. These results suggest that the imbalance between protein phosphatase and kinase that is responsible for the dephosphorylation of Rb is also responsible for the activation of ICE/CED-3 proteases, which in turn is responsible for all the other events associated with apoptosis.
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PMID:The temporal relationship between protein phosphatase, ICE/CED-3 proteases, intracellular acidification, and DNA fragmentation in apoptosis. 901 2

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

The in vivo patterns of CPP32 (Caspase-3) gene expression were determined using an immunohistochemical approach and paraffin-embedded normal human tissues. A rabbit polyclonal antiserum was generated against recombinant human CPP32 protein and shown to be specific by immunoblot analysis of various human tissues and cell lines. CPP32 immunoreactivity was selectively found in certain cell types and was typically present within the cytosol, although occasional cells also contained nuclear immunostaining. CPP32 immunostaining was easily detected, for example, in epidermal keratinocyes, cartilage chondrocytes, bone osteocytes, heart myocardiocytes, vascular smooth muscle cells, bronchial epithelium, hepatocytes, thymocytes, plasma cells, renal tubule epithelium, spermatogonia, prostatic secretory epithelial cells, uterine endometrium and myometrium, mammary ductal epithelial cells, and the gastrointestinal epithelium of the stomach, intestine, and colon. In contrast, little or no CPP32 immunoreactivity was observed in endothelial cells, alveolar pneumocytes, kidney glomeruli, mammary myoepithelial cells, Schwann cells, and most types of brain and spinal cord neurons. Consistent with a role for CPP32 in apoptotic cell death, clear differences in the relative intensity of CPP32 immunostaining were noted in some shorter-lived types of cells compared to longer-lived, including (a) germinal center (high) versus mantle zone (low) B lymphocytes within the secondary follicles of lymph nodes, spleen, and tonsils; (b) mature neutrophils (high) versus myeloid progenitor cells (low) in bone marrow; (c) corpus luteal cells (high) versus follicular granulosa cells (low) in the ovary; and (d) prostate secretory epithelial cells (high) versus basal cells (low). These findings establish for the first time the cell type- and differentiation-specific patterns of expression of an interleukin-1beta converting enzyme/CED-3 (Caspase) family protease.
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PMID:Immunohistochemical analysis of in vivo patterns of expression of CPP32 (Caspase-3), a cell death protease. 910 67

The two genes CED-4 and CED-3 (the nematode homologue of interleukin-1beta converting enzyme, ICE) of Caenorhabditis elegans are implicated in the control of cell death, but the mechanism by which this occurs is unknown. Here we provide evidence that CED-3 and CED-4 both contain sequences with homology to a domain present in RAIDD and the prodomain of certain ICE-like proteases (caspases). This domain is known to establish an interaction between RAIDD and these caspases. Similarly, CED-4 was found to interact with CED-3. Thus, the activity of the death protease CED-3 appears to be controlled by CED-4 through a direct physical interaction.
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PMID:Direct physical interaction between the Caenorhabditis elegans 'death proteins' CED-3 and CED-4. 910 15

Antinuclear autoantibodies (ANAs) derived from patients with systemic autoimmune diseases have proven to be powerful tools in cell and molecular biology, The availability of these autoantibodies has been instrumental in the identification and characterization of a wide range of intracellular proteins involved in essential cellular activities. Recently, these autoantibodies have been used in molecular studies of apoptosis, particularly in the identification of substrates cleaved by proteases of the ICE/CED-3 family during this cell death pathway. The identification of these substrates may help to understand the role of proteolysis in apoptosis. Examples of nuclear autoantigens whose cleavage during apoptosis have been defined using ANAs include the 70 kD protein of the U1 small nuclear ribonucleoprotein particle (U1-70 kD), the nuclear mitotic apparatus protein (NuMA), DNA topoisomerase I, the RNA polymerase I upstream binding factor (UBF), and the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs). The use of ANAs as probes for defining proteolytic events associated with apoptosis promises to yield important insights into the mechanisms driving this cell death pathway.
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PMID:Antinuclear autoantibodies: probes for defining proteolytic events associated with apoptosis. 911 31

B-chronic lymphocytic leukemia (B-CLL) is characterized by the accumulation of long-lived B lymphocytes that express high levels of Bcl-2. We examined the involvement of CED-3/ICE-like proteases in the apoptosis of B-CLL cells. One of the substrates of these proteases is poly(ADP [adenosine 5'-diphosphate]-ribose) polymerase (PARP). The effect of different factors that induce the apoptosis of B-CLL cells on the proteolytic cleavage of PARP has been studied. Treatment of B-CLL cells with different concentrations of dexamethasone (1 to 1,000 micromol/L) induced in a dose-dependent manner the cleavage of PARP. Dexamethasone induced PARP cleavage after 12 hours of incubation, which was almost complete at 48 hours. PARP cleavage during apoptosis of B-CLL cells was studied in cells from eight patients and a correlation was found between cell viability and the degree of PARP cleavage. Incubation in vitro of B-CLL cells with fludarabine for 48 hours induced PARP cleavage in all the cases studied. Protein kinase C (PKC) activation with 100 nmol/L TPA (12-O-tetradecanoylphorbol 13-acetate) or incubation with interleukin-4 (10 ng/mL) prevented either dexamethasone- or fludarabine-induced proteolysis of PARP. Incubation of B-CLL cells with the CED-3/ICE-like protease inhibitor Z-VAD.fmk inhibited spontaneous and dexamethasone-induced PARP cleavage and DNA fragmentation in a dose-dependent manner. Furthermore, Z-VAD.fmk prevented the cytotoxic effect of dexamethasone. These results indicate that CED-3/ICE-like proteases play an important role in the apoptosis of B-CLL cells.
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PMID:Involvement of CED-3/ICE proteases in the apoptosis of B-chronic lymphocytic leukemia cells. 912 45

c-Jun, a signal-transducing transcription factor of the AP-1 family, normally implicated in cell cycle progression, differentiation and cell transformation, recently has also been linked to apoptosis. To explore further the functional roles of c-Jun, a conditional allele was generated by fusion of c-Jun with the hormone-binding domain of the human estrogen receptor (ER). Here we demonstrate that increased c-Jun activity is sufficient to trigger apoptotic cell death in NIH 3T3 fibroblasts. c-Jun-induced apoptosis is evident at high serum levels, but is enhanced further in factor-deprived fibroblasts. Furthermore, apoptosis by c-Jun is not accompanied by an increase in DNA synthesis. Constitutive overexpression of the apoptosis inhibitor protein Bcl-2 delays the c-Jun-mediated cell death. The regions of c-Jun necessary for apoptosis induction include the amino-terminal transactivation and the carboxy-terminal leucine zipper domain, suggesting that c-Jun may activate cell death by acting as a transcriptional regulator. We further show that alpha-fodrin, a substrate of the interleukin 1beta-converting enzyme (ICE) and CED-3 family of cysteine proteases, becomes proteolytically cleaved in cells undergoing cell death by increased c-Jun activity. Moreover, cell-permeable irreversible peptide inhibitors of the ICE/CED-3 family of cysteine proteases prevented the cell death.
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PMID:Induction of apoptosis by the transcription factor c-Jun. 913 Jul 14


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