Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.36 (caspase-1)
 6,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

c-Jun, a signal-transducing transcription factor of the AP-1 family, normally implicated in cell cycle progression, differentiation and cell transformation, recently has also been linked to apoptosis. To explore further the functional roles of c-Jun, a conditional allele was generated by fusion of c-Jun with the hormone-binding domain of the human estrogen receptor (ER). Here we demonstrate that increased c-Jun activity is sufficient to trigger apoptotic cell death in NIH 3T3 fibroblasts. c-Jun-induced apoptosis is evident at high serum levels, but is enhanced further in factor-deprived fibroblasts. Furthermore, apoptosis by c-Jun is not accompanied by an increase in DNA synthesis. Constitutive overexpression of the apoptosis inhibitor protein Bcl-2 delays the c-Jun-mediated cell death. The regions of c-Jun necessary for apoptosis induction include the amino-terminal transactivation and the carboxy-terminal leucine zipper domain, suggesting that c-Jun may activate cell death by acting as a transcriptional regulator. We further show that alpha-fodrin, a substrate of the interleukin 1beta-converting enzyme (ICE) and CED-3 family of cysteine proteases, becomes proteolytically cleaved in cells undergoing cell death by increased c-Jun activity. Moreover, cell-permeable irreversible peptide inhibitors of the ICE/CED-3 family of cysteine proteases prevented the cell death.
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PMID:Induction of apoptosis by the transcription factor c-Jun. 913 Jul 14

Glucocorticoid induces apoptosis in immature lymphocytes which is inhibitable by Bcl-2. Although glucocorticoid-mediated signal transduction is well understood, the mechanism of the induction of apoptosis by the activated glucocorticoid receptor as well as the inhibition of apoptosis by Bcl-2 remains enigmatic. Here we report that overexpressed Bcl-2 relieves the glucocorticoid receptor-mediated repressive function on the AP-1 activity and completely inhibits the activation of CPP32-like cysteine proteases. In contrast, glucocorticoid receptor-mediated transactivation was not affected by Bcl-2. This suggests that glucocorticoid may induce apoptosis by repressing transactivation by AP-1 which is relieved by Bcl-2. Furthermore, we report evidence that, in contrast with CPP32-like proteases, ICE-like proteases are not involved in this apoptotic pathway.
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PMID:Bcl-2 relieves the trans-repressive function of the glucocorticoid receptor and inhibits the activation of CPP32-like cysteine proteases. 916 33

Treatment of U-937 promonocytic cells with the DNA topoisomerase II inhibitor etoposide rapidly caused death by apoptosis, as determined by changes in chromatin structure, production of DNA breaks, nucleosome-sized DNA degradation, decrease in mitochondrial membrane potential and phosphatidyl serine translocation in the plasma membrane, and at the same time induced intracellular acidification. Both the execution of the apoptotic process and the intracellular acidification were reduced by the addition of forskolin plus theophylline or other cAMP increasing agents. These agents also attenuated the induction of apoptosis by camptothecin, heat-shock, cadmium chloride and X-radiation. Although etoposide slightly increased the production of reactive oxygen intermediates, this increase was not prevented by forskolin plus theophylline, and the addition of antioxidant agents failed to inhibit apoptosis. Etoposide caused a great increase in NF-(kappa)B binding activity, which was not prevented by forskolin plus theophylline, while AP-1 binding was little affected by the topoisomerase inhibitor. The treatments did not significantly alter the levels of Bcl-2 and Bax. By contrast, the expression of c-myc, which was very high in untreated U-937 cells and only partially inhibited by etoposide, was rapidly and almost totally abolished by the cAMP increasing agents. Finally, it was observed that etoposide caused a transient dephosphorylation of retinoblastoma (Rb), which was associated with cleavage of poly(ADP-ribose) polymerase (PARP). Both Rb dephosphorylation and PARP cleavage were inhibited by forskolin plus theophylline. The inhibition of Rb (type I) phosphatase and ICE/CED-3-like protease activities, and the abrogation of c-myc expression, are mechanisms which could explain the anti-apoptotic action of cAMP increasing agents in myeloid cells.
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PMID:cAMP increasing agents attenuate the generation of apoptosis by etoposide in promonocytic leukemia cells. 945 37

Apoptosis is a morphologically and biochemically distinct form of cell death which can be triggered by a variety of extracellular agents both during normal developments and in adult pathological states. However, the molecular mechanism of apoptotic cell death due to hypoxia has not been clearly elucidated. In this study, we investigated critical factors involved in hypoxia-induced apoptosis using HepG2, a human hepatocellular carcinoma cell line, as an experimental model. We found that 24 h of exposure of HepG2 cells to hypoxia induced apoptosis, for which de novo protein synthesis was required. Apoptosis was demonstrated by DNA fragmentation and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. Hypoxia-induced apoptosis was associated with a marked induction of c-jun and c-fos messenger RNAs. Electromobility shift assay showed the increased DNA binding activity of AP-1 during hypoxia, suggesting that AP-1 may be involved in the induction of cell death by acting as a transcriptional regulator. A purine analogue, 6-thioguanine (6-TG), significantly blocked the induction of apoptosis by hypoxia. Moreover, the inductive effect of hypoxia on c-jun expression was also inhibited by 6-TG, whereas the levels of c-fos mRNA and its protein were rather strongly increased. Iodoacetamide (IAA), a non-specific inhibitor of ICE family proteases, also has an inhibitory effect on hypoxia-induced apoptosis. These results suggest that the 6-TG-sensitive protein kinase(s)-dependent signaling pathway may be involved in the apoptotic response of HepG2 cells exposed to hypoxia by increasing the level of c-jun and c-fos and the activity of AP-1 and/or by activating ICE family protease(s).
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PMID:Hypoxia-induced apoptosis in human hepatocellular carcinoma cells: a possible involvement of the 6-TG-sensitive protein kinase(s)-dependent signaling pathway. 956 54

Maintenance of mammary epithelial differentiation and milk production during lactation is a consequence of milk removal and the presence of lactogenic hormones, particularly glucocorticoids, insulin and prolactin. After weaning the fall in lactogenic hormones and milk stasis lead to involution, a process that is mainly characterized by three events: (i) downregulation of milk protein gene expression, (ii) loss of epithelial cells by apoptosis and, (iii) tissue remodeling and preparation of the gland for a new pregnancy. Each of these processes is likely to depend on the activity of specific sets of transcription factors in the mammary epithelium and stroma that ensure the timely and spatially coordinated expression of critical gene products such as mediators of apoptosis (e.g., caspase-1 and regulators of tissue remodeling events (e.g., matrix metalloproteinases). Here we describe signal transduction events such as activation of protein kinase A and JNK and changes in the activity of several transcription factors including Stat5, Stat3, NF1, Oct-1, and AP-1 during the early and late phases of mammary gland involution. We discuss their possible role in regulating and coordinating involution with emphasis on the apoptotic process of involution.
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PMID:Transcription factor activities and gene expression during mouse mammary gland involution. 1042 93

Caspase activation and dependence on caspases has been observed in different paradigms of apoptotic cell death in vivo and in vitro. The present study examines the role of caspases in ionizing radiation-induced apoptosis in the developing cerebellum of rats subjected to a single dose (2-Gy gamma rays) of whole-body irradiation at postnatal day 3. Radiation-induced apoptosis in the external granule cell layer, as defined by the presence of cells by extremely condensed, often fragmented nucleus, which were stained with the method of in situ end-labeling of nuclear DNA fragmentation, first appeared at 3 h and peaked at 6 h following irradiation. Increased expression of the precursors of caspase 1 (ICE), 2 (Nedd2), 3 (CPP32), 6 (Mch2), and 8 (Mch5 and FLICE), and increased expression of active caspase 3, as revealed by immunohistochemistry, were observed in the external granule cell layer of the cerebellum. Radiation-induced apoptosis was accompanied by an increase in the expression of the poly(ADP-ribose) polymerase (PARP) fragment of about 89 kD, as revealed by Western blots of cerebellar homogenates. This was not associated with modifications of protein kinase Cdelta and Lamin B. Concomitant injection in the culmen of the cerebellum in irradiated rats of high doses of Y-VAD-cmk, DEV-fmk, or IETD-fmk resulted in decreased expression of the PARP fragment in cerebellar homogenates. This was accompanied by a decrease in the expression of active caspase 3, as shown by immunohistochemistry. These observations suggest caspase activation following ionizing radiation. However, no differences in the number and morphological and biochemical characteristics of apoptotic cells, including strong nuclear and cytoplasmic c-Jun/AP-1 (N) expression, were observed between irradiated and both irradiated and caspase inhibitor-treated rats. Taken together, these observations suggest that the caspases examined are not essential for radiation-induced apoptosis in the developing cerebellum.
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PMID:Role of caspases in ionizing radiation-induced apoptosis in the developing cerebellum. 1059 Jan 78

Despite vaccines and antiviral substances influenza still causes significant morbidity and mortality world wide. Better understanding of the molecular mechanisms of influenza virus replication, pathogenesis and host immune responses is required for the development of more efficient means of prevention and treatment of influenza. Influenza A virus, which replicates in epithelial cells and leukocytes, regulates host cell transcriptional and translational systems and activates, as well as downregulates apoptotic pathways. Influenza A virus infection results in the production of chemotactic (RANTES, MIP-1 alpha, MCP-1, MCP-3, and IP-10), pro-inflammatory (IL-1 beta, IL-6, IL-18, and TNF-alpha), and antiviral (IFN-alpha/beta) cytokines. Cytokine gene expression is associated with the activation of NF-kappa B, AP-1, STAT and IRF signal transducing molecules in influenza A virus-infected cells. In addition of upregulating cytokine gene expression, influenza A virus infection activates caspase-1 enzyme, which is involved in the proteolytic processing of proIL-1 beta and proIL-18 into their biologically active forms. Influenza A virus-induced IFN-alpha/beta is essential in host's antiviral defence by activating the expression of antiviral Mx, PKR and oligoadenylate synthetase genes. IFN-alpha/beta also prolongs T cell survival, upregulates IL-12 and IL-18 receptor gene expression and together with IL-18 stimulates NK and T cell IFN-gamma production and the development of Th1-type immune response.
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PMID:Molecular pathogenesis of influenza A virus infection and virus-induced regulation of cytokine gene expression. 1132

Arsenic (As) is an environmental chemical of high concern for human health. Acute toxicity of arsenic is dependent on its chemical forms and proximity to high local arsenic concentrations is one of the mechanisms for cell death. This study was designed to define acute arsenic-induced stress-related gene expression in vivo. Mice were injected sc with either sodium arsenite [As(III), 100 micromol/kg], sodium arsenate [As(V), 300 micromol/kg], or saline. To examine stress-related gene expression, livers were removed 3 h after arsenic injection for RNA and protein extraction. The Atlas Mouse Stress/Toxicology array revealed that the expression of genes related to stress, DNA damage, and metabolism was altered by acute arsenic treatments. Expression of heme oxygenase 1 (HO-1), a hallmark for arsenic-induced stress, was increased 10-fold, along with increases in heat shock protein-60 (HSP60), DNA damage inducible protein GADD45, and the DNA excision repair protein ERCC1. Downregulation of certain cytochrome P450 enzymes occurred with arsenic treatment. Multiprobe RNase protection assay revealed the activation of the c-Jun/AP-1 transcription complex after arsenic treatments. Western blot analysis further confirmed the enhanced production of arsenic-induced stress proteins such as HO-1, HSP70, HSP90, metallothionein, the metal-responsive transcription factor MTF-1, nuclear factor kappa B and c-Jun/AP-1. Increases in caspase-1 and cytokines such as tumor necrosis factor-alpha (TNF-alpha) and macrophage inflammatory protein-2 were also evident. In summary, this study profiled the gene expression pattern in mice treated with inorganic arsenicals, which adds to our understanding of acute arsenic poisoning and toxicity.
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PMID:Stress-related gene expression in mice treated with inorganic arsenicals. 1135 40

Based on our recent observation that enhanced IL-18 expression positively correlates with malignant skin tumors, such as SCC and melanoma, we examined the possible role of UVB, known to be associated with skin cancer development, in the enhancement of IL-18 production using primary human epidermal keratinocytes and human keratinocyte cell line HaCaT. After cells were exposed to UVB irradiation in vitro, IL-18 production was examined by Northern blot analysis and ELISA, and it was found that IL-18 production is enhanced by UVB irradiation in a dose- and time-dependent manner. In addition, we confirmed that it is functionally active form of IL-18 using the inhibitor of caspase-1. The effect of UVB irradiation was blocked by antioxidant, N-acetyl-L-cysteine (NAC), which suggested the involvement of reactive oxygen intermediates (ROI) in the signal transduction of UVB irradiation-enhanced IL-18 synthesis. We also found that UVB irradiation increased AP-1 binding activity by using EMSA with AP-1-specific oligonucleotide. Furthermore, inhibitors of UVB-induced AP-1 activity, such as PD98059, blocked enhanced IL-18 production, indicating that AP-1 activation is required for UVB-induced IL-18 production. Taken together, our results suggest that UVB irradiation-enhanced IL-18 production is selectively mediated through the generation of ROI and the activation of AP-1.
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PMID:The enhanced IL-18 production by UVB irradiation requires ROI and AP-1 signaling in human keratinocyte cell line (HaCaT). 1238 30

Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is an adaptor molecule that mediates inflammatory and apoptotic signals. Although the role of ASC in caspase-1-mediated IL-1beta and IL-18 maturation is well known, ASC also induces NF-kappaB activation and cytokine gene expression in human cells. In this study, we investigated the molecular mechanism and repertoire of ASC-induced gene expression in human cells. We found that the specific activation of ASC induced AP-1 activity, which was required for optimal IL8 promoter activity. ASC activation also induced STAT3-, but not STAT1-, IFN-stimulated gene factor 3- or NF-AT-dependent reporter gene expression. The ASC-mediated AP-1 activation was NF-kappaB-independent and primarily cell-autonomous response, whereas the STAT3 activation required NF-kappaB activation and was mediated by a factor that can act in a paracrine manner. ASC-mediated AP-1 activation was inhibited by chemical or protein inhibitors for caspase-8, caspase-8-targeting small-interfering RNA, and p38 and JNK inhibitors, but not by a caspase-1 inhibitor, caspase-9 or Fas-associated death domain protein (FADD) dominant-negative mutants, FADD- or RICK-targeting small-interfering RNAs, or a MEK inhibitor, indicating that the ASC-induced AP-1 activation is mediated by caspase-8, p38, and JNK, but does not require caspase-1, caspase-9, FADD, RICK, or ERK. DNA microarray analyses identified 75 genes that were induced by ASC activation. A large proportion of them was related to transcription (23%), inflammation (21%), or cell death (16%), indicating that ASC is a potent inducer of inflammatory and cell death-related genes. This is the first report of ASC-mediated AP-1 activation and the repertoire of genes induced downstream of ASC activation.
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PMID:Mechanism and repertoire of ASC-mediated gene expression. 1949 89


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