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 reaper gene (rpr) is important for the activation of apoptosis in Drosophila. To investigate whether rpr expression is sufficient to induce apoptosis, transgenic flies were generated that express rpr complementary DNA or the rpr open reading frame in cells that normally live. Transcription of rpr from a heat-inducible promoter rapidly caused wide-spread ectopic apoptosis and organismal death. Ectopic overexpression of rpr in the developing retina resulted in eye ablation. The occurrence of cell death was highly sensitive to the dosage of the transgene. Because cell death induced by the protein encoded by rpr (RPR) could be blocked by the baculovirus p35 protein, RPR appears to activate a death program mediated by a ced-3/ICE (interleukin-1 converting enzyme)-like protease.
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PMID:Cell killing by the Drosophila gene reaper. 862 96

A genomic interval at 75C1,2 is required for programmed cell death in Drosophila. We identified a new activator of apoptosis, grim, which maps between two previously identified cell death genes in this region reaper (rpr) and head involution defective (hid). Expression of grim RNA coincided with the onset of programmed cell death at all stages of embryonic development, whereas ectopic induction of grim triggered extensive apoptosis in both transgenic animals and in cell culture. Cell killing by grim was blocked by coexpression of p35, a viral product that inactivates ICE-like proteases, and did not require the functions of rpr or hid. The predicted grim protein shares an amino-terminal motif in common with rpr. However, grim was sufficient to elicit apoptosis in at least one context, where rpr was not. The grim gene product might thus function in a parallel circuit of cell death signaling that ultimately activates a common set of downstream apoptotic effectors.
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PMID:grim, a novel cell death gene in Drosophila. 869 37

The baculovirus gene p35 inhibits virus-induced apoptosis in insect cells. p35 can also inhibit developmentally programmed cell death in Caenorhabditis elegans and Drosophila, mammalian neuronal cell death induced by serum or NGF deprivation, and Fas- and tumor necrosis factor (TNF)-induced apoptosis in mammalian cells, indicating that p35 may interrupt an evolutionally conserved component of the death machinery. Recently it has been shown that p35 protein functions as an inhibitor of ICE/CED-3 cysteine protease family that seem to play an important role in an apoptotic pathway. This observation indicates that p35 may inhibit apoptosis by directly blocking the activities of these cysteine proteases in diverse animals.
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PMID:[Inhibition of apoptosis by a baculovirus p35 gene]. 874 86

Apoptosis is induced upon infection of SF-21 cells by mutants of the baculovirus Autographa californica nuclear polyhedrosis virus (AcMNPV) lacking a functional p35 gene which encodes a stoichiometric inhibitor of members of the interleukin-1beta converting enzyme family of cysteine proteases (N.J. Bump et al, Science 269:1885-1888, 1995; R.J. Clem, M. Fechheimer, and L.K. Miller, Science 254:1388-1390, 1991). We found that transfection of SF-21 cells with the AcMNPV ie-1 gene was sufficient to induce apoptosis, which was characterized by fragmentation of cellular DNA into oligonucleosomal fragments and apoptotic body formation. No signs of apoptosis were observed in Trichoplusia ni TN-368 cells transfected with ie-1, a result which is consistent with the observation that p35 mutants of AcMNPV do not induce apoptosis in this cell line. Cotransfection of SF-21 cells with p35 blocked ie-1-induced apoptosis, indicating that expression of ie-1 activates apoptosis through a p35-inhibitable cysteine protease pathway. Cotransfection with Cp-iap, an active member of another family of antiapoptotic inhibitors of apoptosis (iaps), also inhibited IE1-induced apoptosis. Thus, ie-1 may participate in inducing apoptosis in AcMNPV-infected cells, although the dependence of induction on DNA replication suggests that ie-1 is not the direct apoptotic signal during infection. The ie-1 gene product, IE1, is known to be a potent transactivator of baculovirus gene expression that interacts with specific palindromic sequences which can act as transcriptional enhancers and as origins of DNA replication in transient assays.
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PMID:Induction of apoptosis by baculovirus transactivator IE1. 879 58

In liver, apoptosis is a physiological process involved in the clearance of injured cells and in homeostatic control [1]. However, in patients with viral fulminant hepatitis or with nonacute liver diseases [2], dramatic liver failure or secondary cirrhosis results from the death of hepatocytes, which express the cell-surface receptor Fas, by apoptosis. To date, treatment of fulminant hepatitis relies mainly on orthotopic liver transplantation, which is limited by immunological complications and graft availability. Unravelling the molecular mechanisms that underlie acute liver failure could allow the design of an appropriate therapy. Ligand-bound Fas and tumour necrosis factor alpha (TNF-alpha) induce hepatic apoptosis in mice [3-6]. In various cell types, Fas- or TNF-alpha-induced apoptosis is blocked by viral proteins (such as p35 and CrmA) as well as by a decoy peptide (YVADcmk) [7-11], suggesting that these mechanisms of apoptosis involve ICE (interleukin-1 beta converting enzyme)-like proteases. Here, we report that, in vivo, pre-treatment of mice with YVADcmk protects them from the lethal effect of anti-Fas antibody and from liver failure induced by injection of TNF-alpha. Remarkably, YVADcmk administration is also highly effective in rescuing mice that have been pretreated with anti-Fas antibody from rapid death, despite extensive hepatic apoptosis. This dramatic curative effect could be of clinical benefit for the treatment of viral and inflammatory liver diseases.
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PMID:ICE inhibitor YVADcmk is a potent therapeutic agent against in vivo liver apoptosis. 880 75

The product of the reaper (rpr) gene is required for programmed cell death in Drosophila. We examined rpr expression during ectopic cell deaths caused by ionizing radiation or aberrant development. In both instances, dramatic induction of rpr expression was observed. A genomic fragment upstream of rpr confers this regulatory behavior upon a lacZ reporter transgene. In a model cell culture system, conditional expression of REAPER is sufficient to induce massive apoptosis that can be prevented by the anti-apoptotic protein p35. Overall, these results suggest that diverse signals converge at, or upstream of, rpr-associated transcriptional regulatory elements that can function to initiate a common apoptotic pathway involving ICE-like protease activity.
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PMID:Activation of the reaper gene during ectopic cell killing in Drosophila. 894 86

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

Expression of the reaper gene (rpr) correlates with the initiation of apoptosis in Drosophila melanogaster. Transient expression of rpr in the lepidopteran SF-21 cell line induced apoptosis displaying nuclear condensation and fragmentation, oligonucleosomal ladder formation, cell surface blebbing, and apoptotic body formation. Inhibitors of ICE-family proteases p35 and crmA, as well as members of the iap class of genes, Op-iap and D-iap2, but not bcl-2 family members, blocked rpr-induced apoptosis. Mutational analysis of rpr provided no support for the proposed sequence similarity of Reaper and death domain proteins. Mutations in the N-terminal region of Reaper, which displays sequence similarity to Hid and Grim, other Drosophila gene products correlated with the initiation of apoptosis, suggested that these residues might be functionally important. The mammalian cDNA encoding FADD (Fas-associating protein with a death domain) also induced cell death in SF-21 cells, but death progressed more slowly and with features which distinguished it from rpr-induced apoptosis. Several bcl-2 family members delayed or blocked FADD-induced cellular death. Thus, apoptosis initiated by Reaper progressed by a faster path which appeared to differ from that of FADD-induced apoptosis.
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PMID:Characterization of reaper- and FADD-induced apoptosis in a lepidopteran cell line. 900 Dec 20

Activation of ICE/Ced-3 family proteases (caspases) has been proposed to mediate both the granule exocytosis and Fas-Fas ligand pathways of rapid target cell death by cytotoxic T lymphocytes. In agreement with this model, two peptide fluoromethyl ketone caspase inhibitors and baculovirus p35 blocked apoptotic nuclear damage and target cell lysis by the CTL-mediated Fas-Fas ligand pathway. The peptide caspase inhibitors also blocked drug-induced apoptotic cell death in tumor cells. In contrast, the caspase inhibitors blocked CTL granule exocytosis-induced target apoptotic nuclear damage, but did not inhibit target lysis. These results are consistent with recent demonstrations that granzyme B can activate caspases leading to apoptotic nuclear damage, but show that target cell lysis by CTL granule exocytosis occurs by a caspase-independent pathway.
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PMID:Target cell lysis by CTL granule exocytosis is independent of ICE/Ced-3 family proteases. 904 42

The Bcl-2 and Bcl-x proteins suppress programmed cell death, whereas Bax promotes apoptosis. We investigated the pattern of expression of Bcl-2, Bax and Bcl-x during neuronal differentiation and development. All three proteins were widely expressed in neonatal rats but, in the adult, Bax levels were 20- to 140-fold lower in the cerebral cortex, cerebellum and heart muscle, whereas Bcl-x was not downregulated in any of the tissues examined. In the cerebral cortex and cerebellum, the decrease in Bax levels occurred after the period of developmental cell death. Further, microinjection of a Bax expression vector into cultured sympathetic neurons, which depend on nerve growth factor for survival, induced apoptosis in the presence of survival factor and increased the rate of cell death after nerve growth factor withdrawal. This effect could be blocked by co-injection of an expression vector for Bcl-xL or for the baculovirus p35 protein, an inhibitor of caspases (ICE-like proteases). These results suggest that, during development, the sensitivity of neurons to signals that induce apoptosis may be regulated by modulating Bax levels and that Bax-induced death requires caspase activity.
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PMID:Bax promotes neuronal cell death and is downregulated during the development of the nervous system. 910 10


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