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)

Since mammalian cardiac myocytes essentially rely on aerobic energy metabolism, it has been assumed that cardiocytes die in a catastrophic breakdown of cellular homeostasis (i.e. necrosis), if oxygen supply remains below a critical limit. Recent observations, however, indicate that a process of gene-directed cellular suicide (i.e. apoptosis) is activated in terminally differentiated cardiocytes of the adult mammalian heart by ischemia and reperfusion, and by cardiac overload as well. Apoptosis or programmed cell death is an actively regulated process of cellular self destruction, which requires energy and de novo gene expression, and which is directed by an inborn genetic program. The final result of this program is the fragmentation of nuclear DNA into typical 'nucleosomal ladders', while the functional integrity of the cell membrane and of other cellular organelles is still maintained. The critical step in this regulated apoptotic DNA fragmentation is the proteolytic inactivation of poly-[ADP-ribose]-polymerase (PARP) by a group of cysteine proteases with some structural homologies to interleukin-1 beta-converting enzyme (ICE-related proteases [IRPs] such as apopain, yama and others). PARP catalyzes the ADP-ribosylation of nuclear proteins at the sites of spontaneous DNA strand breaks and thereby facilitates the repair of this DNA damage. IRP-mediated destruction of PARP, the 'supervisor of the genome', can be induced by activation of membrane receptors (e.g. FAS or APOI) and other signals, and is inhibited by activation of 'anti-death genes' (e.g. bcl-2). Overload-triggered myocyte apoptosis appears to contribute to the transition to cardiac failure, which can be prevented by therapeutic hemodynamic unloading. In myocardial ischemia, the activation of the apoptotic program in cardiocytes does not exclude their final destiny to catastrophic necrosis with release of cytosolic enzymes, but might be considered as an adaptive process in hypoperfused ventricular zones, sacrificing some jeopardized myocytes to regulated apoptosis, which may be less arrhythmogenic than necrosis with the primary disturbance of membrane function.
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PMID:Apoptosis in the heart: when and why? 897 66

The ability of both acute and chronic ethanol exposures to elicit cell death within specific embryonic and adult tissues is believed to partly underlie ethanol's pathogenicity; however, the mechanism underlying this cell death is unknown. This study partially characterized the mechanism of ethanol-induced neural crest cell death in a chick embryo model of fetal alcohol syndrome. In situ DNA end-labeling demonstrated this cell death was apoptotic and occurred at embryonic ethanol levels as low as 42 mM. Regardless of the initial exposure time, this apoptosis always appeared at a distinct developmental time point simultaneous with the normal deletion of a cranial neural crest subset. This suggested that ethanol might act through aberrant activation of the endogenous death pathway; however, ethanol exposure failed to induce two components of this pathway, the homeotic transcription factor msx-2 and the growth factor bone morphogenetic protein 4. Both endogenous and ethanol-induced death were blocked by local application of an interleukin-1beta converting enzyme/CED-3 protease (caspase) inhibitor, showing that the two paths converge mechanistically and suggesting the potential to prevent this aspect of ethanol's teratogenicity. Ethanol exposure did not significantly alter cell proliferation within neural crest-populated regions, suggesting that susceptibility to ethanol-induced death did not involve exit from the cell cycle. Apoptotic deletion of cranial neural crest could partially explain the craniofacial deficits characteristic of the fetal alcohol syndrome.
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PMID:Ethanol-induced neural crest apoptosis is coincident with their endogenous death, but is mechanistically distinct. 951 99

Activation of heat shock factor (HSF) 1-DNA binding and inducible heat shock protein (hsp) 70 (also called hsp72) expression enables cells to resist various forms of stress and survive. Fas, a membrane-bound protein, is a central proapoptotic factor; its activation leads to a cascade of events, resulting in programmed cell death. These two mechanisms with contradictory functions, promoting either cell survival or death, were examined for their potential to inhibit each other's activation. Induction of FAS-mediated signaling was followed by a rapid decrease in HSF1-DNA binding and inducible hsp70 expression. Inhibition of HSF1-DNA binding was demonstrated to be based on absent hyperphosphorylation of HSF1 during FAS signaling. These effects of FAS activation on the HSF1/hsp70 stress response were blocked by ICE (caspase 1) inhibitors, suggesting an ICE-mediated process. Furthermore, inhibition of HSF1/hsp70 was accompanied by an increase in apoptosis rates from 20% to 50% in response to heat stress. When analyzing the effects of HSF1/hsp70 activation on Fas-mediated apoptosis, protection from apoptosis was seen in cells with induced hsp70 protein levels, but not in cells that were just induced for HSF1-DNA binding. Thus, we conclude that inhibition of HSF1/hsp70 stress response during Fas-mediated apoptosis and vice versa may facilitate a cell to pass a previously chosen pathway, stress resistance or apoptosis, without the influence of inhibitory signals.
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PMID:Activation of Fas inhibits heat-induced activation of HSF1 and up-regulation of hsp70. 1022 27

We have previously shown that nitric oxide (NO) induces apoptosis in different human neoplastic lymphoid cells through caspase activation. Here we studied the NO-mediated apoptosis in human breast cancer cell lines derived from primary tumor (BT-20) or from metastasis (MCF-7). NO donor glycerol trinitrate (GTN) induced apoptosis in both cell lines which was completely abrogated after pretreatment with the broad spectrum caspase inhibitor zVAD-fmk. NO triggered also a time-dependent activation of caspase-1, caspase-3, and caspase-6 in these cells. Moreover, NO caused a release of mitochondrial protein cytochrome c into the cytosol, an increase in the number of cells with low mitochondrial transmembrane potential and with high level of reactive oxygen species production. However, NO did not induce mRNA expression of CD95 (APO-1/Fas) ligand. FAS-associated phosphatase-1 (FAP-1) molecule was constitutively expressed at the mRNA level and did not show any changes upon NO treatment in both breast cancer cell lines. The expression of the pro-apoptotic protein Bax and of the anti-apoptotic protein Bcl-2 remained unchanged in MCF-7 and BT-20 cells upon GTN treatment. We suggest that the mechanism of NO-mediated activation of the caspase cascade and subsequent apoptosis in human breast cancer cells required mitochondrial damage (in particular, cytochrome c release, disruption of mitochondrial transmembrane potential and generation of reactive oxygen species) but not the activation of the CD95/CD95L pathway.
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PMID:Nitric oxide-mediated apoptosis in human breast cancer cells requires changes in mitochondrial functions and is independent of CD95 (APO-1/Fas). 1060 55

A RIP-like protein, RIP3, has recently been reported that contains an N-terminal kinase domain and a novel C-terminal domain that promotes apoptosis. These experiments further characterize RIP3-mediated apoptosis and NF-kappaB activation. Northern blots indicate that rip3 mRNA displays a restricted pattern of expression including regions of the adult central nervous system. The rip3 gene was localized by fluorescent in situ hybridization to human chromosome 14q11.2, a region frequently altered in several types of neoplasia. RIP3-mediated apoptosis was inhibited by Bcl-2, Bcl-x(L), dominant-negative FADD, as well as the general caspase inhibitor Z-VAD. Further dissection of caspase involvement in RIP3-induced apoptosis indicated inhibition by the more specific inhibitors Z-DEVD (caspase-3, -6, -7, -8, and -10) and Z-VDVAD (caspase-2). However, caspase-1, -6, -8 and -9 inhibitors had little or no effect on RIP3-mediated apoptosis. Mutational analysis of RIP3 revealed that the C-terminus of RIP3 contributed to its apoptotic activity. This region is similar, but distinct, to the death domain found in many pro-apoptotic receptors and adapter proteins, including FAS, FADD, TNFR1, and RIP. Furthermore, point mutations of RIP3 at amino acids conserved among death domains, abrogated its apoptotic activity. RIP3 was localized by immunofluorescence to the mitochondrion and may play a key role in the mitochondrial disruptions often associated with apoptosis.
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PMID:The RIP-like kinase, RIP3, induces apoptosis and NF-kappaB nuclear translocation and localizes to mitochondria. 1081 27

Activation of heat shock factor (HSF)-1 DNA binding and heat shock protein (hsp)-70 expression enable resistance of cells to various forms of stress and maintain cell survival. Fas, a membrane-bound protein, is a central pro-apoptotic factor. Its activation leads to a cascade of events resulting in programmed cell death. Herein, these two mechanisms with contrary functions, promoting either cell survival or death, were addressed for their potential to inhibit each other's activation. Induction of Fas-mediated signalling was followed by a rapid decrease of HSF1 DNA binding and inducible hsp70 expression. Inhibition of HSF1 DNA binding was demonstrated to be based on absent hyperphosphorylation of HSF1 during FAS-signalling. These effects of Fas-activation on the HSF1/hsp70 stress response were blocked by ICE (caspase 1)-inhibitors, suggesting an ICE-mediated process. Furthermore, inhibition of HSF1/hsp70 was accompanied by an increase of apoptosis rates from 20% to 50% in response to heat stress. When analyzing Fas-mediated apoptosis in the presence of HSF1/hsp70 activation, decreased apoptosis rates were detected with induced expression of hsp70 but not with activation of HSF1-DNA binding alone. Thus, we conclude that inhibition of the HSF1/hsp70 stress response during Fas-mediated apoptosis and vice versa may facilitate a cell to pass a previously chosen pathway, stress resistance or apoptosis.
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PMID:[Reciprocal modification of Fas activation and stress protein response decides apoptosis or resistance development of cells]. 1089 90

While the elimination of hepatitis B virus (HBV) is a common phenomenon at the end of the acute phase of disease, the persistence of HBV is characteristic for chronic hepatitis (CHB). Recent evidence indicates that the elimination of HBV is achieved by FAS/FAS-L induced apoptosis of infected hepatocytes. The aim of this study was to test the hypothesis that HBV persistence in the hepatocytes of CHB patients is due to the delayed onset of apoptosis caused by altered FAS/FAS-L interactions between lymphocytes and hepatocytes. The expression of FAS, FAS-L, BAX, BCL-2, ICE and PCNA in the liver biopsies of 55 patients (14 HBsAg positive, 20 patients with alcoholic hepatopathy, 21 patients with other hepatopathies) was tested by immunohistochemistry. Apoptosis of hepatocytes was evaluated by morphological as well as by TUNEL method. The results were correlated with a grading/staging score and analysed statistically using a one way analysis of variance and the Duncan test. Significantly highernumbers of BAX positive hepatocytes were observed in HBsAg positive patients when compared to control groups. Similarly, both BAX and FAS positive lymphocytes were more frequent in HBsAg positive patients. FAS-L positive lymphocytes and hepatocytes were numerous in all patient groups. Increased numbers of BAX positive hepatocytes in CHB may reflect the increased readiness of these cells to undergo apoptosis. However, the increased numbers of both BAX and FAS positive lymphocytes in CHB suggest that these cells may be particularly sensitive to FAS-L mediated apoptosis potentially resulting in lowered viability of these lymphocytes. This may explain, at least in part, the defective removal of virus-infected cells in chronic hepatitis. However, we cannot rule out the possibility that survival of hepatocytes during CHB may be due to other mechanisms such as defects in apoptosis activation triggered by CD40, defects involving DNase and/or other caspases downstream in the apoptotic cascade within these cells, or to defects in CTL function.
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PMID:Apoptosis-related proteins, BCL-2, BAX, FAS, FAS-L and PCNA in liver biopsies of patients with chronic hepatitis B virus infection. 1093 89

Tumor necrosis factor alpha (TNF-alpha) is a proinflammatory cytokine that induces apoptosis in a number of cell systems, including osteoblasts. Transforming growth factor beta1 (TGF-beta1) is an abundant growth factor that is known to stimulate bone formation. This study was designed to examine the role of TGF-beta1 on TNF-alpha-induced apoptosis in murine osteoblastic MC3T3-E1 cells. Total RNA was extracted from MC3T3-E1 cells treated with 20 ng/ml of TNF-alpha, 10 ng/ml of TGF-beta1, or combination, for 6 h. TNF-alpha exerted a variety of effects on the apoptotic gene expression in osteoblasts. Ribonuclease protection assays (RPA) revealed that TNF-alpha upregulated the mRNA levels of caspase-1, -7, -11, -12, and FAS. Western blot analysis showed enhanced processing of caspase-1, -7, -11, and -12, with the appearance of their activated enzymes 24 h after TNF-alpha treatment. In addition, caspase-3-like activity was significantly activated following TNF-alpha treatment. Levels of cleaved poly(ADP-ribose) polymerase and FAS protein were also elevated by TNF-alpha. Finally, Hoechst staining, terminal deoxynucleotidyl-transferase nick-end labeling (TUNEL) assay, and oligonucleosome ELISA all indicated that TNF-alpha induced apoptosis. In contrast, the addition of TGF-beta1 attenuated all of the aforementioned effects of TNF-alpha. Our results demonstrate that TGF-beta1 can decrease TNF-alpha-induced apoptosis in murine osteoblasts at least in part by attenuating TNF-alpha-induced caspase gene expression.
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PMID:TGF-beta1 inhibits multiple caspases induced by TNF-alpha in murine osteoblastic MC3T3-E1 cells. 1243 78

In experimental autoimmune encephalomyelitis, the acute phase of the disease is produced by T-helper lymphocyte type 1 (TH1), which produces mainly TNFalpha and IFNgamma. Recovery from the disease is mediated by T-helper lymphocyte types 2 and 3 (TH2/TH3), which, among other cytokines, produce transforming growth factor beta (TGFbeta). To address the influence of TGFbeta on TH1-induced gene expression, microarray technology was used on murine primary microglial cells stimulated with IFNgamma and TNFalpha in the absence or presence of TGFbeta. The resulting data from an investigation of up to 5,500 genes provided the notion that TGFbeta prevents the induction of a proinflammatory gene program within microglia exposed to a TH1 milieu. TH1 cytokines upregulated 175 genes comprising cytokine, chemokine, and genes involved in host response to infection and the TNFalpha/IFNgamma intracellular signaling pathway. It is observed that TGFbeta inhibits expression of 25% of the TNFalpha/IFNgamma-induced genes and a further 66 TNFalpha/IFNgamma-independent genes. The focus of TGFbeta inhibition is observed to be directed in genes involved in chemotaxis (IL-15, CXCL1, CXCL2, CCL3, CCL4, CCL5, CCL9), chemokine receptors (CCR5, CCR9), LIF receptor, and FPR2, and on genes mediating cell migration (MMP9, MMP13, MacMARCKS, endothelin receptor B, Ena/VASP, Gas7), apoptosis (FAS, TNF, TNF receptor, caspase-1 and -11), and host response to infection (toll-like receptor 6, Mx-1, and MARCO). Taken collectively, the data strongly suggest that one of the main effects of TGFbeta is to impair cell entry into the CNS and to hinder migration of microglia in the CNS parenchyma.
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PMID:TGFbeta directs gene expression of activated microglia to an anti-inflammatory phenotype strongly focusing on chemokine genes and cell migratory genes. 1460 63

Lexatumumab, a human agonistic monoclonal antibody against tumor necrosis factor (TNF)-related apoptosis-inducing ligand receptor-2 (TRAIL-R2), is a promising molecular-targeted therapeutic agent. Our past study indicated that low concentrations of doxorubicin sensitized renal cell carcinoma (RCC) cells to lexatumumab-mediated apoptosis. The present study was designed to examine the cellular and molecular effects of lexatumumab and anthracyclines in RCC cells. The treatment of human RCC cells with lexatumumab in combination with anthracyclines, epirubicin, and pirarubicin had a synergistic cytotoxicity. A marked synergistic apoptosis was induced by lexatumumab in combination with epirubicin or pirarubicin. Epirubicin and pirarubicin significantly increased the TRAIL-R2 expression at both the mRNA and the protein levels. The combination-induced cytotoxicity was significantly suppressed by the human recombinant DR5:Fc chimeric protein. To further explore the molecular mechanisms in this synergistic cytotoxicity with lexatumumab and anthracyclines, the changes in 84 apoptosis-related genes were evaluated by a quantitative polymerase chain reaction (PCR) array. Among these genes, 18 (CD40LG, FASLG, LTA, TNSF7, FAS, BAG3, BAK1, BAX, BID, BIK, BCL10, caspase-1, caspase-5, caspase-6, caspase-10, TNF receptor-associated factor 1, PYCARD, and CIDEA) were significantly upregulated and eight (TNF receptor-associated factor 4, TNFRSF11B, TNF, BCL2, BCL2L1, BNIP3L, caspase-9, and DAPK1) were downregulated at mRNA levels in RCC cells cotreated with lexatumumab and epirubicin. Furthermore, the upregulation of mRNA levels of PYCARD and CIDEA was confirmed using real-time reverse transcriptase-PCR analysis. The present study demonstrates that anthracylines sensitize RCC cells to lexatumumab-mediated apoptosis by inducing TRAIL-R2 expression, and the utility of PCR array to elucidate the mechanism of synergistic apoptosis.
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PMID:Delineation of apoptotic genes for synergistic apoptosis of lexatumumab and anthracyclines in human renal cell carcinoma cells by polymerase chain reaction array. 2220 56


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