Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A small number of cellular proteins present in the nucleus, cytosol, and membrane fraction are specifically cleaved by the interleukin-1beta-converting enzyme (ICE)-like family of proteases during apoptosis. Previous results have demonstrated that one of these, the cytoskeletal protein actin, is degraded in rat PC12 pheochromocytoma cells upon serum withdrawal. Extracts from etoposide-treated U937 cells are also capable of cleaving actin. It was assumed that cleavage of actin represented a general phenomenon, and a mechanism coordinating proteolytic, endonucleolytic, and morphological aspects of apoptosis was proposed. We demonstrate here that actin is resistant to degradation in several different human cells induced to undergo apoptosis in response to a variety of stimuli, including Fas ligation, serum withdrawal, cytotoxic T-cell killing, and DNA damage. On the other hand, cell-free extracts from these cells and the ICE-like protease CPP32 were capable of cleaving actin in vitro. We conclude that while actin contains cleavage sites for ICE-like proteases, it is not degraded in vivo in human cells either because of lack of access of these proteases to actin or due to the presence of other factors that prevent degradation.
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PMID:Resistance of actin to cleavage during apoptosis. 899 Jan 78

Cell death due to reoxygenation after hypoxia was characterized in primary cultured hepatocytes. Fluorescence and electron microscopic analyses of reoxygenated hepatocytes revealed morphological characteristics of apoptosis, including chromatin condensation, nuclear fragmentation, and formation of apoptotic bodies. Few necrotic hepatocytes, defined by loss of plasma membrane integrity, mitochondrial swelling, and formation of large vacuoles, were observed. Activation of interleukin-1 beta-converting enzyme (ICE)-like and CPP32/Yama-like proteases, which are known to drive apoptosis, was observed during reoxygenation, and addition of their respective inhibitors inhibited the induction of apoptosis, indicating the involvement of ICE family proteases in apoptosis by reoxygenation. Production of oxygen radicals was enhanced by reoxygenation of hypoxic cells, and reoxygenation-induced apoptosis was inhibited by oxygen radical scavengers, suggesting a role for reactive oxygen species as a triggering factor in cell death. Electrophoretic analysis revealed the presence of 50-kb DNA fragments but not oligonucleosomal DNA fragments in reoxygenation-induced apoptotic hepatocytes.
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PMID:Involvement of ICE family proteases in apoptosis induced by reoxygenation of hypoxic hepatocytes. 899 38

Employing the degenerate primer-dependent polymerase chain reaction approach used recently to clone human Mch2, we have identified and cloned the insect Spodoptera frugiperda target of the baculovirus antiapoptotic protein p35. This protein named Sf caspase-1 belongs to the family of caspases and is highly related to human Mch3 and CPP32 in sequence and specific activity. The proenzyme of Sf caspase-1 is 299 amino acids in length and can undergo autocatalytic processing in Escherichia coli to an active enzyme heterocomplex. Autoprocessing occurs at Asp-28, Asp-184, and Asp-195 to generate the large p19/p18 and small p12 subunits. Sf caspase-1 is able to induce apoptosis in Sf9 cells and is capable of cleaving p35 to similar sized fragments as observed with extracts from p35 null mutant baculovirus-infected Sf9 cells. Sf caspase-1 activity is potently inhibited by p35, suggesting that it is an important target of this antiapoptotic protein. Finally, the Sf9 nuclear immunophilin FKBP46 was identified as a death-associated substrate for Sf caspase-1.
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PMID:Spodoptera frugiperda caspase-1, a novel insect death protease that cleaves the nuclear immunophilin FKBP46, is the target of the baculovirus antiapoptotic protein p35. 899 5

The response of eukaryotic cells to ionizing radiation (IR) includes induction of apoptosis. However, the signals that regulate this response are unknown. The present studies demonstrate that IR treatment of U-937 cells is associated with: (i) internucleosomal DNA fragmentation; (ii) cleavage of poly(ADP-ribose) polymerase; (iii) cleavage of protein kinase C delta; and (iv) induction of an Ac-DEVD-p-nitroanilide cleaving activity. Overexpression of the cowpox protein CrmA blocked tumor necrosis factor (TNF)-induced apoptosis but had no effect on IR-induced DNA fragmentation or cleavage of poly(ADP-ribose) polymerase and protein kinase C delta. By contrast, overexpression of the baculovirus p35 protein blocked both IR- and TNF-induced apoptosis. The results further demonstrate that the IR-induced proteolytic activity is directly inhibited by the addition of purified recombinant p35, but not by CrmA. We show that the CPP32 protease is sensitive to p35 and not CrmA. We also show that IR induces activation of CPP32 and that this event, like induction of apoptosis, is sensitive to overexpression of p35 and not CrmA. These findings indicate that IR-induced apoptosis involves activation of CPP32 and that this CrmA-insensitive apoptotic pathway is distinct from those induced by TNF and certain other stimuli.
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PMID:Activation of a CrmA-insensitive, p35-sensitive pathway in ionizing radiation-induced apoptosis. 899 87

The interleukin-1 beta-converting enzyme (ICE) family of proteases is an important component of the mechanism of the apoptotic process, but the physiologic roles of the different homologs during apoptosis remain unclear. Significant information about the roles of proteolysis in apoptosis will be gained through identification of the distal substrates through which these proteases achieve their pro-apoptotic effects. Identification of these substrates therefore remains an important challenge. A subset of autoantibodies from patients with systemic lupus erythematosus (SLE) recognize molecules that are specifically cleaved early during apoptosis. Several of the identified autoantigens are nuclear proteins (PARP, U1-70 kDa, and DNA-PKcs) that are substrates for CPP32 in vitro and in apoptotic cells. Of note, these substrates are catalytic proteins involved in homeostatic pathways, suggesting that abolition of homeostasis is one fundamental feature ensuring the rapid irreversibility of the apoptotic process. Identification of the other substrates for this protease family will provide the tools to assess the roles of the different proteases in apoptotic death.
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PMID:Macromolecular substrates for the ICE-like proteases during apoptosis. 901 54

Activation of proteolytic enzymes, including cysteine proteases of the ced-3/ICE family, is a characteristic feature of the apoptotic program. In contrast, the role of the proteasome as the major nonlysosomal machinery to degrade or process proteins by ATP/ubiquitin-dependent proteolysis in this process is less clear. In human leukemic HL60 cells, inhibition of proteasome-mediated proteolysis by specific proteasomal inhibitors leads to the rapid induction of apoptosis as judged by morphological changes as well as by nuclear condensation and DNA fragmentation. HL60 apoptosis is due to activation of CPP32, a member of the ced-3/ICE family of cysteine proteases, and appears to occur independently from ICE activity. HL60 apoptosis is accompanied by an increase in the concentration of the cyclin-dependent kinase inhibitor p27Kip1. Labeling of the cells by the TUNEL technique demonstrates that HL60 cells undergoing apoptosis are primarily in the G1 phase of the cell cycle. Proteasomal activity therefore appears to be required in proliferating, but not in quiescent, HL60 cells for cell survival as well as normal progression through the cell cycle.
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PMID:Activation of the cell death program by inhibition of proteasome function. 902 46

Some chemotherapeutic agents, as well as TNF and Fas, induce apoptotic cell death in tumor cells, but the cellular components involved in the process have not yet been identified. Interleukin 1 beta converting enzyme (ICE) is a mammalian homolog of CED-3, a protein required for programmed cell death in nematode Caenorhabditis elegans. We found that a selective inhibitor of ICE/ced 3 family proteases, benzyloxycarbonyl Asp CH2OC(O) 2 6,-dichlorobenzene (Z-Asp-CH2-DCB). completely blocked the apoptotic cell death of human leukemia cells caused by etoposide, camptothecin, 1-beta-D-arabinofuranosyl cytosine (Ara-C) and adriamycin. Moreover, in antitumor agent-treated U937 cells, an ICE-like (CPP32-like) protease was strongly activated. These results indicate that ICE/ ced 3 family proteases are involved in antitumor agent-induced apoptosis. Activation of ICE family proteases plays a key role in apoptosis. However, the subsequent mechanisms resulting in apoptosis are largely unknown. We identified actin as a substrate of ICE family proteases. Cleavage of actin and other substrate proteins by ICE family proteases could be critical in the ongoing process of antitumor agent-induced apoptosis in tumor cells.
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PMID:[Involvement of ICE/CED 3 family proteases in antitumor agent-induced apoptosis]. 903 Feb 33

During amphibian metamorphosis, the tail and gills that are useful in aquatic life but inappropriate for terrestrial activity are induced to degenerate completely in several days by endogenous thyroid hormone (TH). The dramatic resorption of the tadpole tail has attracted a good deal of attention as an experimental system of cell death, but the mechanism has not been well characterized. To facilitate in vitro analysis, we have established a myoblast cell line (XLT-15) derived from the Xenopus laevis tadpole tail. This cultured cell line died in response to TH and exhibited positive TUNEL reaction and internucleosomal DNA cleavage. Simultaneously, expression of the Xenopus CPP32/apopain/Yama gene was up-regulated by TH in the cell line as it is in regressing tadpole tail, whereas interleukin-1beta-converting enzyme (ICE) mRNA is around 1 copy/cell in tail and undetectable in XLT-15 cells. A CPP32/apopain/Yama inhibitor (acetyl-Asp-Glu-Val-Asp-aldehyde) prevented TH-induced apoptosis of XLT-15 cells, but an ICE inhibitor (acetyl-Tyr-Val-Ala-Asp-aldehyde) did not. These results suggested that an increase of CPP32/apopain/Yama gene expression is involved in TH-dependent apoptosis of XLT-15 and tadpole tail resorption during metamorphosis.
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PMID:Induction of apoptosis and CPP32 expression by thyroid hormone in a myoblastic cell line derived from tadpole tail. 903 May 78

Several members of the IL-1beta-converting enzyme (ICE) family of proteases recently have been implicated in the intracellular cascade mediating the apoptotic death of various cell types. It is unclear, however, whether ICE-related proteases are involved in apoptosis of mammalian neurons and, if so, how they are activated. Here we report the cloning of an ICE-related protease (IRP) from rat brain, which displays strong sequence identity to human CPP32. In situ hybridization histochemistry reveals that this IRP mRNA is expressed in neuron-enriched regions of the developing and adult rat brain but is profoundly downregulated in the adult (compared with developing) brain. To investigate whether this IRP is involved in the death of neurons in the developing brain, we studied IRP expression in cultured cerebellar granule neurons. In cultured cerebellar granule neurons, reduction of extracellular K+ reliably induces apoptosis and stimulates overexpression of IRP mRNA. The latter is especially prominent 4 hr after switching from high K+ to low K+ medium. The expression of IRP mRNA was maintained at this level for at least 8 hr and was followed by apoptotic death of these neurons. Induction of IRP mRNA and cell death are blocked completely by adding depolarizing concentrations of K+ </=90 min after switching to low K+ medium (i.e., before the commitment point for apoptosis) and partially blocked by brain-derived neurotrophic factor (BDNF), which also partially rescues granule neurons from low K+-induced apoptosis. In addition, overexpression of IRP cDNA in HeLa cells results in cell death accompanied by strong internucleosomal cleavage of DNA, a typical feature of apoptosis. Finally, we detected cleavage of the putative death substrate poly (ADP-ribose) polymerase (PARP), beginning 8 hr after changing from high K+ to low K+ medium, coinciding with the time course of induced expression of the IRP gene. Our data suggest that transcriptional activation of IRP could be one of the mechanisms involved in the apoptotic death of cerebellar granule neurons.
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PMID:Cloning and expression of a rat brain interleukin-1beta-converting enzyme (ICE)-related protease (IRP) and its possible role in apoptosis of cultured cerebellar granule neurons. 903 Jun 16

The DNA-dependent protein kinase (DNA-PK) is a serine/threonine kinase linked to DNA repair and V(D)J recombination. It is composed of a 460-kDa catalytic subunit (DNA-PKcs) and a 70/86-kDa heterodimeric regulatory component that is identical with the human autoantigen Ku. The regulatory subunit targets the catalytic subunit to the free ends of dsDNA breaks. Since apoptosis is associated with internucleosomal chromatin fragmentation and creation of dsDNA breaks, we examined whether the biochemical amounts of either DNA-PKcs or Ku changed during apoptosis mediated by the cell surface receptor Fas. We found that the catalytic subunit was cleaved into several smaller polypeptides early in apoptosis. In contrast to DNA-PKcs, Ku was neither cleaved nor decreased in amount during apoptosis. We then extended our in vivo results to a cellfree system. Cytosolic extracts derived from apoptotic cells were able to cleave DNA-PKcs into polypeptides of sizes identical with those seen in vivo, and this cleavage was inhibited by the cysteine protease inhibitors iodoacetamide and N-ethylmaleimide. Furthermore, DNA-PKcs was cleaved in vitro by purified apopain (CPP32), but not IL-1beta-converting enzyme. Cleavage was also inhibited by the specific tetrapeptide DEVD (amino acids 2709-2712 of the DNA-PKcs sequence), suggesting a candidate position for protease action. Finally, we found that the catalytic activity of DNA-PKcs was decreased in apoptotic cells. We conclude that DNA-PKcs is subject to selective cleavage by proteases during apoptosis. Cleavage of DNA-PKcs may represent a mechanism for regulating the function of DNA-dependent kinase during programmed cell death.
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PMID:The DNA-dependent protein kinase catalytic subunit (p460) is cleaved during Fas-mediated apoptosis in Jurkat cells. 903 52


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