Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 mechanism by which IFN-gamma inhibits tumor cell growth has not been fully understood. Here we report that IFN-gamma up-regulated the expression of Fas and Fas ligand (FasL) on HT29 cells, a human colon adenocarcinoma cell line, and subsequently induced apoptosis of these cells. The kinetics of cell death in IFN-gamma-treated HT29 cells paralleled the increase in the levels of Fas and FasL expression. We further show that IFN-gamma up-regulated the expression of Fas and FasL in STAT1-transfected U3A cells but not in STAT1-deficient U3A cells. Correspondingly, IFN-gamma induced cell death in STAT1-transfected U3A cells but not in STAT1-deficient U3A cells. IFN-gamma-induced cell death was inhibited by caspase-1 inhibitors. Our results suggest that cell growth inhibition by IFN-gamma is due to apoptosis mediated by Fas and FasL interaction.
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PMID:IFN-gamma induces cell growth inhibition by Fas-mediated apoptosis: requirement of STAT1 protein for up-regulation of Fas and FasL expression. 966 98

Werner's syndrome (WS) is an inherited disease with clinical symptoms which resemble premature aging. The Werner's syndrome gene (WRN), which is located on human chromosome 8p12, encodes a predicted protein of 1432 amino acids and shows significant similarity to DNA helicases. We have cloned the full-length mouse cDNA homologue of the human WRN gene encoding a predicted protein of 1320 amino acids and have obtained a full-length 70 kb genomic clone containing the moWRN gene. This gene has been mapped to chromosome 8A3 in mice. The expression of the moWRN gene was increased during apoptosis after IL-2 deprivation, and decreased in the spleen of aged mice. Lymphoid cells isolated from a patient with WS exhibited increased apoptosis after incubation with anti-Fas but not after incubation with the topoisomerase inhibitor VP16. RNase protection reviled dysregulation of the ICE family of apoptosis molecules in the WS cell line. These results indicate that the WS helicase is involved in certain pathways of apoptosis, and defective WS gene expression leads to accumulation of cells that are highly susceptibility to Fas-induced apoptosis.
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PMID:Effect of age and apoptosis on the mouse homologue of the huWRN gene. 968 77

Murine L929 fibrosarcoma cells were transfected with the human Fas (APO-1/CD95) receptor, and the role of various caspases in Fas-mediated cell death was assessed. Proteolytic activation of procaspase-3 and -7 was shown by Western analysis. Acetyl-Tyr-Val-Ala-Asp-chloromethylketone and benzyloxycarbonyl-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-fluoromethylketone++ +, tetrapeptide inhibitors of caspase-1- and caspase-3-like proteases, respectively, failed to block Fas-induced apoptosis. Unexpectedly, the broad-spectrum caspase inhibitors benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone and benzyloxycarbonyl-Asp(OMe)-fluoromethylketone rendered the cells even more sensitive to Fas-mediated cell death, as measured after 18 h incubation. However, when the process was followed microscopically, it became clear that anti-Fas-induced apoptosis of Fas-transfected L929 cells was blocked during the first 3 h, and subsequently the cells died by necrosis. As in tumor necrosis factor (TNF)-induced necrosis, Fas treatment led to accumulation of reactive oxygen radicals, and Fas-mediated necrosis was inhibited by the oxygen radical scavenger butylated hydroxyanisole. However, in contrast to TNF, anti-Fas did not activate the nuclear factor kappaB under these necrotic conditions. These results demonstrate the existence of two different pathways originating from the Fas receptor, one rapidly leading to apoptosis, and, if this apoptotic pathway is blocked by caspase inhibitors, a second directing the cells to necrosis and involving oxygen radical production.
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PMID:Dual signaling of the Fas receptor: initiation of both apoptotic and necrotic cell death pathways. 973 Aug 93

Mice exposed to 100% O2 die after 3 or 4 d with diffuse alveolar damage and alveolar edema. Extensive cell death is evident by electron microscopy in the alveolar septa, affecting both endothelial and epithelial cells. The damaged cells show features of both apoptosis (condensation and margination of chromatin) and necrosis (disruption of the plasma membrane). The electrophoretic pattern of lung DNA indicates both internucleosomal fragmentation, characteristic of apoptosis, and overall degradation, characteristic of necrosis. Hyperoxia induces a marked increase in RNA or protein levels of p53, bax, bcl-x, and Fas, which are known to be expressed in certain types of apoptosis. However, we did not detect an increased activity of proteases belonging to the apoptosis "executioner" machinery, such as CPP32 (caspase 3), ICE (caspase 1), or cathepsin D. Furthermore, administration of an ICE-like protease inhibitor did not significantly enhance the resistance to oxygen. Additionally, neither p53-deficient mice nor lpr mice (Fas null) manifested an increased resistance to hyperoxia-induced lung damage. These results show that both necrosis and apoptosis contribute to cell death during hyperoxia. Multiple apoptotic pathways seem to be involved in this, and an antiapoptotic strategy does not attenuate alveolar damage.
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PMID:Oxygen toxicity in mouse lung: pathways to cell death. 976 53

Both caspase-1- and caspase-3-like activities are required for Fas-mediated apoptosis. However, the role of caspase-1 and caspase-3 in mediating Fas-induced cell death is not clear. We assessed the contributions of these caspases to Fas signaling in hepatocyte cell death in vitro. Although wild-type, caspase-1(-/-), and caspase-3(-/-) hepatocytes were killed at a similar rate when cocultured with FasL expressing NIH 3T3 cells, caspase-3(-/-) hepatocytes displayed drastically different morphological changes as well as significantly delayed DNA fragmentation. For both wild-type and caspase-1(-/-) apoptotic hepatocytes, typical apoptotic features such as cytoplasmic blebbing and nuclear fragmentation were seen within 6 hr, but neither event was observed for caspase-3(-/-) hepatocytes. We extended these studies to thymocytes and found that apoptotic caspase-3(-/-) thymocytes exhibited similar "abnormal" morphological changes and delayed DNA fragmentation observed in hepatocytes. Furthermore, the cleavage of various caspase substrates implicated in mediating apoptotic events, including gelsolin, fodrin, laminB, and DFF45/ICAD, was delayed or absent. The altered cleavage of these key substrates is likely responsible for the aberrant apoptosis observed in both hepatocytes and thymocytes deficient in caspase-3.
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PMID:Caspase-3 controls both cytoplasmic and nuclear events associated with Fas-mediated apoptosis in vivo. 981 49

The angiotensin-converting enzyme inhibitor captopril has been shown to inhibit fibrogenesis in the lung, but the mechanisms underlying this action are unclear. Apoptosis of lung epithelial cells is believed to be involved in the pathogenesis of pulmonary fibrosis. For these reasons, we studied the effect of captopril on Fas-induced apoptosis in a human lung epithelial cell line. Monoclonal antibodies that activate the Fas receptor induced epithelial cell apoptosis as detected by chromatin condensation, nuclear fragmentation, DNA fragmentation, and increased activities of caspase-1 and -3. Apoptosis was not induced by isotype-matched nonimmune mouse immunoglobulins or nonactivating anti-Fas monoclonal antibodies. When applied simultaneously with anti-Fas antibodies, 50 ng/ml of captopril completely abrogated apoptotic indexes based on morphology, DNA fragmentation, and inducible caspase-1 activity and significantly decreased the inducible activity of caspase-3. Inhibition of apoptosis by captopril was concentration dependent, with an IC50 of 70 pg/ml. These data suggest that the inhibitory actions of captopril on pulmonary fibrosis may be related to prevention of lung epithelial cell apoptosis.
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PMID:Captopril inhibits apoptosis in human lung epithelial cells: a potential antifibrotic mechanism. 981 21

The aim of the present study was to correlate the islet expression of the apoptosis-associated factors Fas/Apo-1, FasL, ICE and perforin with the progression of beta-cell destruction in non-obese diabetic (NOD) mice. For this purpose, thymus and isolated pancreatic islets from male and female NOD mice of 5 and 15 weeks of age were subjected to immunoblot analysis. Islet expression of the Fas/Apo-1 receptor and ICE were increased in islets from female mice 15 weeks of age as compared to corresponding males. No Fas/Apo-1 or ICE signal was observed in the 5-week-old mice. The expression of perforin increased both in islets and in thymus with age and female gender. Islet expression of FasL could not be detected. Culture of isolated islets from NMRI mice in the presence of interleukin-1beta (IL-1beta) induced the expression of ICE. The present results support a direct role of the Fas/FasL and the perforin systems in the autoimmune destruction of insulin producing cells [corrected].
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PMID:Islet expression of perforin, Fas/Apo-1 and interleukin-1 converting enzyme (ICE) in non-obese diabetic (NOD) mice. 984 Jun 79

Deregulation of cell death pathways is an important feature of tumorigenesis. Fas, a member of the tumor necrosis factor receptor superfamily, is a transmembrane protein that can transduce cell death signals via a proteolytic cascade upon crosslinking or ligand binding. Fas has been implicated in the cell turnover of normal stratified squamous epithelia. To determine if altered Fas mediated cell death pathways participate in epithelial tumorigenesis, we examined squamous cell carcinoma (SCC) lines for sensitivity to Fas ligand (FasL) or an agonistic anti-Fas antibody. All cell lines examined were resistant to FasL mediated cell death. The carcinoma cell line SCC71 was also highly resistant to anti-Fas antibody. Another line, SCC9, underwent rapid cell death with characteristic features of apoptosis after exposure to anti-Fas antibody. However, binding of both FasL and anti-Fas antibody recruited downstream effector molecules to the Fas cytoplasmic domain in both SCC9 and SCC71 cells. Inhibition of the caspase 3- but not the ICE family of cell death proteases blocked apoptosis in SCC9 cells independently of expression of the anti-apoptotic protein bcl2. We concluded that Fas differentially mediates apoptosis in SCC lines by activation of caspase 3 family members but independent of bcl2 expression.
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PMID:Anti-Fas antibody differentially regulates apoptosis in Fas ligand resistant carcinoma lines via the caspase 3 family of cell death proteases but independently of bcl2 expression. 985 79

Concanavalin A (Con A)-induced hepatitis is an experimental hepatitis model in which hepatic injury is caused by the action of cytokines produced by T cells. Using IFN-gamma-deficient mice, we previously demonstrated that IFN-gamma plays a central role in Con A-induced hepatitis. Here, we show that development of the disease is completely suppressed in gld/gld mice, in which Fas ligand is defective. In contrast, suppression of the disease in Ipr/Ipr mice was incomplete, since a small amount of the fas mRNA was produced in these mice. The data indicate that activation of the Fas/Fas ligand system is a necessary step in the development of Con A-induced hepatitis. Furthermore, we found that not only fas but also caspase-1 expression was reduced in IFN-gamma-deficient mice. Since caspase-1 is an integral component of Fas signal transduction, these observations suggest that IFN-gamma-induced activation of both fas and caspase-1 expression causes enhancement of hepatocyte apoptosis resulting in the development of hepatitis.
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PMID:Involvement of Fas/Fas ligand system-mediated apoptosis in the development of concanavalin A-induced hepatitis. 986 46

Apoptosis is well accepted as a type of cell death occurring in the development of mammalian muscles, but the death of adult myofibres in neuromuscular disorders and exercise-induced muscle damage is usually explained in terms of muscle necrosis. The current view that apoptosis precedes necrosis in death of dystrophin-deficient muscle fibres of mdx mouse has been well substantiated. Moreover, apoptotic myonuclei have been reported to increase in mdx mice 2 days after spontaneous exercise. To investigate the contribution of apoptosis to exercise-induced damage of normal muscle fibre a time-course analysis has been performed in adult C57BL/6 mice. Groups of five mice were sacrificed immediately after the end of the exercise, and after a rest period of 6 or 96 h. The amount of apoptosis in leg muscles was assessed by electron microscopy, by the terminal deoxynucleotidyl transferase assay and by electrophoretic detection of fragmented DNA; the expression of Bcl-2, Bax, Fas, ICE, p53 and ubiquitin was examined by immunohistochemistry and Western blot. Absent in muscles of normal 'sedentary' mice, apoptotic myonuclei peak in muscles of normal mice after a night of spontaneous wheel-running (4% +/- 3.5, immediately and 2.5% +/- 1.8 after 6 h rest, P < 0.05 vs non-runner mice); they then decrease but are present 4 days later (0.8% +/- 1.5). Satellite cells are also involved in the apoptotic process. Myofibre content of Bcl-2 decreases whereas Bax, Fas, ICE and ubiquitin modify their pattern of expression in correlation with the changes in apoptotic myonuclei. Apoptosis of endothelial cells is present after the night of wheel-running and with a twofold increase 4 days later (1.5 +/- 2.3 and 4.8 +/- 4.4 P < 0.05, respectively). Satellite cells are also involved in the apoptotic process. Thus, spontaneous running in unaccustomed mice increases the number of apoptotic nuclei in adult muscle fibres and in endothelial cells. It remains to be established whether muscle apoptosis is restricted to the repair mechanisms, as often suggested in many pathologic processes, or it is also part of pathogenesis of muscle damage. Regardless of whether these results are extended to human dystrophies, the clinical implications in terms of secondary pathogenetic mechanisms and muscle training are obvious.
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PMID:Apoptosis of myofibres and satellite cells: exercise-induced damage in skeletal muscle of the mouse. 988 62


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