Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.60 (caspase-7)
 920 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Four human cell lines derived from Ewing's sarcoma, EW-7, EW-1, COH and ORS, were investigated to establish the effects of human recombinant interferon-alpha2a and human recombinant interferon-beta on cell proliferation and apoptosis. All four cell lines were much more sensitive to the antiproliferative effects of IFN-beta than of IFN-alpha. Analysis of the early signals triggered by IFN-alpha and IFN-beta demonstrated that the two IFNs were similarly effective in inducing tyrosine phosphorylation of the Jak-1 and Tyk-2 kinases and the transcription factors Stat-1 and Stat-2. Interestingly, an additional rapid phosphorylation of Stat-1 on serine was observed after IFN-beta treatment, with concomitant activation of p38 mitogen-activated protein kinase. In these cells, Stat-1 Ser727 phosphorylation in response to IFN-beta was found to be impaired by p38 MAPkinase inhibitor (SB203580). IFN-beta induced the formation of the Interferon Stimulated Gene Factor 3 complex more efficiently than IFN-alpha, as well as sustained induction of IRF-1, which may account for its greater induction of 2'5'oligo(A)synthetase and greater inhibition of cell proliferation. IFN-beta, but not IFN-alpha, induced apoptosis in wild-type p53 EW-7 and COH cell lines, but not in the mutated p53 EW-1 or ORS cell lines. The apoptosis induced by IFN-beta in EW-7 and COH cell lines appeared to be mediated by IRF-1 and involved the activation of caspase-7. Ectopic expression of IRF-1 induced apoptosis in all four cell lines which correlated with the activation of caspase-7 and with the downregulation of the Bcl-2 oncoprotein, as observed for IFN-beta-induced apoptosis in parental EW-7 and COH cell lines.
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PMID:IFN-beta induces serine phosphorylation of Stat-1 in Ewing's sarcoma cells and mediates apoptosis via induction of IRF-1 and activation of caspase-7. 1091 94

STAT1 is a transcription factor that plays a crucial role in signaling by interferons (IFNs). In this study we demonstrated that inhibitors of histone deacetylase (HDAC) activity, butyrate, trichostatin A, and suberoylanilide hydroxamic acid, prevented IFNgamma-induced JAK1 activation, STAT1 phosphorylation, its nuclear translocation, and STAT1-dependent gene activation. Furthermore, we showed that silencing of HDAC1, HDAC2, and HDAC3 through RNA interference markedly decreased IFNgamma-driven gene activation and that overexpression of HDAC1, HDAC2, and HDAC3 enhanced STAT1-dependent transcriptional activity. Our data therefore established the essential role of deacetylase activity in STAT1 signaling. Induction of IRF-1 by IFNgamma requires functional STAT1 signaling and was abrogated by butyrate, trichostatin A, suberoylanilide hydroxamic acid, and STAT1 small interfering RNA. In contrast, silencing of STAT1 did not interfere with IFNgamma-induced expression of STAT2 and caspase-7, and HDAC inhibitors did not preclude IFNgamma-induced expression of STAT1, STAT2, and caspase-7, suggesting that HDAC inhibitors impede the expression of IFNgamma target genes whose expression depends on STAT1 but do not interfere with STAT1-independent signaling by IFNgamma. Finally, we showed that inhibitors of deacetylase activity sensitized colon cancer cells to IFNgamma-induced apoptosis through cooperative negative regulation of Bcl-x expression, demonstrating that interruption of the balance between STAT1-dependent and STAT1-independent signaling significantly alters the biological activity of IFNgamma.
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PMID:Requirement of histone deacetylase activity for signaling by STAT1. 1512 34

The GAGE family of highly related tumor antigens is expressed in a variety of tumors. This albeit silent gene expression resulted in resistance of cells to various apoptotic agents such as Fas, interferon-gamma, Taxol, or gamma-radiation. We now report that GAGE overexpression in either HeLa (expressing endogenous GAGE) or HEK293 (devoid of GAGE expression) rendered those cells unsusceptible to cell death induced by IFN-gamma. We investigated the underlying mechanism of GAGE-induced cell survival upon treatment with IFN-gamma in this report. We showed that GAGE overexpression resulted in down-regulation of a key player of IFN-gamma-signaling pathway, interferon regulatory factor 1 (IRF1), and its target genes caspase-1 and caspase-7. An interaction between GAGE and IRF1 is detected in cells. Furthermore, GAGE interacted with a multifunctional protein nucleophosmin (NPM)/B23 and increased its abundance by stabilizing the protein. Increased level of NPM/B23 in conjunction with decreased level of IRF1 could aid GAGE-induced resistance to IFN-gamma. Our results suggest that GAGE could rescue cell death induced by IFN-gamma by altering the level of key players in cell death pathways. As GAGE is silent in most healthy tissues, targeting GAGE could result in therapeutic interventions in cancer therapy.
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PMID:GAGE, an antiapoptotic protein binds and modulates the expression of nucleophosmin/B23 and interferon regulatory factor 1. 1964 96