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)

Selective transcription of the insulin gene in pancreatic beta cells is regulated by its enhancer, located between nucleotides -340 and -91 relative to the transcription start site. One of the principal control elements within the enhancer is found between nucleotides -100 and -91 (GCCATCTGCT, referred to as the insulin control element [ICE]) and is regulated by both positive- and negative-acting transcription factors in the helix-loop-helix (HLH) family. It was previously shown that the c-jun proto-oncogene can repress insulin gene transcription. We have found that c-jun inhibits ICE-stimulated transcription. Inhibition of ICE-directed transcription is mediated by sequences within the carboxy-terminal region of the protein. These c-jun sequences span an activation domain and the basic leucine zipper DNA binding-dimerization region of the protein. Both regions of c-jun are conserved within the other members of the jun family: junB and junD. These proteins also suppress ICE-mediated transcription. The jun proteins do not appear to inhibit insulin gene transcription by binding directly to the ICE. c-jun and junB also block the trans-activation potential of two skeletal muscle-specific HLH proteins, MyoD and myogenin. These results suggests that the jun proteins may be common transcription control factors used in skeletal muscle and pancreatic beta cells to regulate HLH-mediated activity. We discuss the possible significance of these observations to insulin gene transcription in pancreatic beta cells.
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PMID:c-jun inhibits transcriptional activation by the insulin enhancer, and the insulin control element is the target of control. 826 34

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

The proto-oncogene bcl-2 and a bcl-2-related gene bcl-x prevent apoptotic cell death induced by various treatments. Although a mechanism has been proposed that involves Bcl-2 activity on reactive oxygen species (ROS), we find that expression of Bcl-2 or Bcl-xL prevents cell death induced by withdrawal of oxygen (hypoxia) and that the cell death does not involve ROS, suggesting that Bcl-2 or Bcl-xL exerts an anti-cell death function by a mechanism other than through regulation of ROS activity. Using electron microscopy, and confocal and non-confocal fluorescence microscopy, we show that hypoxia induces both necrosis and apoptosis. Overexpression of Bcl-2 or Bcl-xL blocks hypoxia-induced apoptosis and, although to a lesser extent, necrosis. The anti-apoptotic proteins Bcl-2 and Bcl-xL effectively inhibit KCN-induced cell death which is characterized by necrotic features including apparently intact chromatin, remarkable mitochondrial swelling with loss of crista structure and loss of plasma membrane integrity. The necrotic cell death is also inhibited by inhibitors of ICE (interleukin-1 beta converting enzyme)(-like) proteases, the common mediators of apoptosis. These results indicate that Bcl-2/Bcl-xL and ICE(-like) proteases modulate both apoptotic and at least some forms of necrotic cell death, suggesting that both cell death pathways involve some common mediators.
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PMID:Bcl-2 and Bcl-xL block apoptosis as well as necrosis: possible involvement of common mediators in apoptotic and necrotic signal transduction pathways. 920 97

c-Myc is a transcriptional activator implicated in the control of cell proliferation, differentiation and transformation, but is also involved in the regulation of programmed cell death, apoptosis. Despite intensive research, the molecular mechanisms by which c-Myc triggers and executes cell death remain still elusive. Here, we made use of Rat 1A MycER cells expressing a conditionally active c-Myc protein and tested first the hypothesis that ornithine decarboxylase (ODC), which is a transcriptional target of c-Myc, were a mediator of c-Myc-induced apoptosis. However, our results show that the activity of ODC is not required for the c-Myc-mediated apoptosis to occur in these cells. We also found that the expression of p53, p21waf1/cip1, Bcl-2, Bax, Bcl-xL, Bad and cyclins D1, E, A and B did not show any significant changes following c-Myc induction. But, our studies revealed that the c-Myc induced apoptosis is associated with a specific cleavage of poly(ADPribose) polymerase (PARP), suggesting that a cysteine protease of the ICE/CED-3 family is involved. Moreover, we found that the cysteine protease CPP32/Caspase-3, which is known to cleave PARP, is processed from its inactive form to an active protease composed of 17 and 12 kDa subunits; whilst Ich-1/Caspase-2 belonging to another subset of this protease family was not processed/ activated following c-Myc activation. The activation of CPP32 and apoptotic cell death were inhibited by addition of Z-VAD-fmk, a universal inhibitor of ICE-like proteases. Further, a selective inhibitor of CPP32-like proteases (Z-DEVD-fmk) partly inhibited apoptosis. These results provide evidence that the ICE/CED3-family proteases, CPP32 and likely others, play a critical role in the execution of a nuclear proto-oncogene, c-Myc-induced apoptosis.
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PMID:Involvement of CPP32/Caspase-3 in c-Myc-induced apoptosis. 946 64

Infection of erythroid-lineage cells by human parvovirus B19 is characterized by a gradual cytocidal effect. Accumulating evidence now implicates the nonstructural (NS1) protein of the virus in cytotoxicity, but the mechanism underlying the NS1-induced cell death is not known. Using a stringent regulatory system, we demonstrate that NS1 cytotoxicity is closely related to apoptosis, as evidenced by cell morphology, genomic DNA fragmentation, and cell cycle analysis with the human erythroleukemia cell line K562 and the erythropoietin-dependent megakaryocytic cell line UT-7/Epo. Apoptosis was significantly inhibited by an interleukin-1beta (IL-1beta)-converting enzyme (ICE)/CED-3 family protease inhibitor, Ac-DEVD-CHO (CPP32; caspase 3), whereas a similar inhibitor of ICE (caspase 1), Ac-YVAD-CHO, had no effect. Furthermore, stable expression of the human Bcl-2 proto-oncogene resulted in near-total protection from cell death in response to NS1 induction. Mutations engineered into the nucleoside triphosphate-binding domain of NS1 significantly rescued cells from NS1-induced apoptosis without having any effect on NS1-induced activation of the IL-6 gene expression which is mediated by NF-kappaB. Furthermore, using pentoxifylline, an inhibitor of NF-kappaB activation, we demonstrate that the NF-kappaB-mediated IL-6 activation by NS1 is uncoupled from the apoptotic pathway. This functional dissection indicates a complexity underlying the biochemical function of human parvovirus NS1 in transcriptional activation and induction of apoptosis. Our findings indicate that NS1 of parvovirus B19 induces cell death by apoptosis in at least erythroid-lineage cells by a pathway that involves caspase 3, whose activation may be a key event during NS1-induced cell death.
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PMID:Human parvovirus B19 nonstructural (NS1) protein induces apoptosis in erythroid lineage cells. 952 24

Patients with genetic defects of the cyclic (c) adenosine-monophosphate (AMP)-signaling pathway and those with neonatal-onset multisystem inflammatory disease (NOMID) develop tumor-like lesions of the long bones. The molecular basis of this similarity is unknown. NOMID is caused by inappropriate caspase-1 activity, which in turn activates the inflammasome. The present study demonstrates that NOMID bone lesions are derived from the same osteoblast progenitor cells that form fibroblastoid tumors in mice and humans with defects that lead to increased cAMP-dependent protein kinase A (PKA) signaling. NOMID tumor cells showed high PKA activity, and an increase in their cAMP signaling led to PKA-specific activation of caspase-1. Increased PKA led to inflammation-independent activation of caspase-1 via over-expression of the proto-oncogene (and early osteoblast factor) Ets-1. In NOMID tumor cells, as in cells with defective PKA regulation, increased prostaglandin E2 (PGE2) led to increased cAMP levels and activation of Wnt signaling, like in other states of inappropriate PKA activity. Caspase-1 and PGE2 inhibition led to a decrease in cell proliferation of both NOMID and cells with abnormal PKA. These data reveal a previously unsuspected link between abnormal cAMP signaling and defective regulation of the inflammasome and suggest that caspase-1 and PGE2 inhibition may be therapeutic targets in bone lesions associated with defects of these two pathways.
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PMID:Protein kinase A regulates caspase-1 via Ets-1 in bone stromal cell-derived lesions: a link between cyclic AMP and pro-inflammatory pathways in osteoblast progenitors. 2094 Jan 46