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 roles of interferons (IFNs) in apoptosis are not fully understood. In this study we show that in the U937 monoblastic leukemia cell line, pretreatment with IFN-gamma enhanced sensitivity to apoptosis triggered by gamma-irradiation or antitumor agents (etoposide or adriamycin), as well as by anti-Fas antibody. In addition, IFN-gamma caused an increased expression of the interleukin-1 beta-converting enzyme (Ice) gene, following strong induction of the interferon regulatory factor-1 (IRF-1) gene, the product of which is a transcriptional activator of the Ice gene. An inhibitor of ICE/Ced-3 family proteases, Z-Asp-CH2-DCB, blocked apoptosis in control cells as well as in IFN-gamma-pretreated cells. These results suggest that enhanced susceptibility of IFN-gamma-pretreated cells to apoptosis is mediated through the induction of Ice by IRF-1. This pathway is not affected by interleukin-1 beta (IL-1 beta) since neutralizing antibody against IL-1 beta failed to suppress the IFN-gamma-mediated enhancement of cell death, and IL-1 beta itself did not mimic the effect of IFN-gamma.
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PMID:Interferon-gamma induces Ice gene expression and enhances cellular susceptibility to apoptosis in the U937 leukemia cell line. 895 78

Interferon regulatory factor-1 (IRF-1) is a transcription factor regulating the expression of several cytokines. Using IRF-1 knockout (KO) mice, the role of IRF-1 in the production and activity of IL-18 was evaluated. Administration of IL-12 or concanavalin A significantly increased levels of circulating IL-18 in wild-type (WT), but not in IRF-1 KO mice. However, despite these differences in circulating IL-18 levels, no or only minor differences in constitutive or inducible IL-18 mRNA and tissue-associated protein levels were observed between WT and IRF-1 KO mice. On the other hand, we observed that constitutive and inducible levels of the IL-18-processing enzyme caspase-1 were markedly reduced in the spleen and the liver of IRF-1 KO compared to WT mice. In addition, both constitutive and inducible liver mRNA levels for the IL-18 binding protein (IL-18BP), a specific IL-18 antagonist, were significantly lower in IRF-1 KO than in WT mice. Compared to IL-12, IL-18 only weakly induced IRF-1 mRNA in cultured splenocytes. However, IL-18-induced IFN-gamma production was strongly reduced in splenocytes from IRF-1 KO compared to WT cells. In conclusion, IRF-1 regulates IL-18 production and activity mostly by modulating expression of caspase-1 and IL-18BP. In addition, IRF-1 participates in the induction of IFN-gamma by IL-18.
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PMID:Role of interferon regulatory factor-1 in the regulation of IL-18 production and activity. 1118 Jan

Although biotherapy of gastroenteropancreatic neuroendocrine tumors (NET) provides excellent control for the hypersecretion syndrome, tumor regression is rarely observed, implying the need for novel antiproliferative strategies. Here, we demonstrate that human pancreatic QGP-1 NET cells express functionally intact interferon-gamma (IFN-gamma) receptors and downstream effectors, including the putative tumor suppressor interferon regulatory factor-1 (IRF-1). IFN-gamma treatment profoundly inhibited anchorage-dependent and anchorage-independent growth of QGP-1 cells. Concomitant with the onset of growth inhibition, apoptotic cells were detected in cell cycle analyses of IFN-gamma treated cultures. Apoptosis was confirmed by evaluation of DNA fragmentation and PARP cleavage. Immunoblots of IFN-gamma treated QGP-1 cells revealed a substantial upregulation of caspase-1, followed by the appearance of active proteolytic fragments of caspase-3, suggesting that autocatalytic activation of caspase-1 might initiate the caspase cascade. Apoptosis induction by IFN-gamma was also observed in two of four primary cultures established from tumors of patients with for- and midgut NETs, respectively. Taken together our results characterize IFN-gamma as a potent proapoptotic stimulus in a subset of gastrointestinal NETs and suggest an IRF-1 mediated induction of caspase-1 as a relevant underlying mechanism. Based on these results, the potential of IFN-gamma in experimental biotherapeutic treatment of NETs can be further explored.
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PMID:Interferon-gamma inhibits growth of human neuroendocrine carcinoma cells via induction of apoptosis. 1237 Jul 65

Caspases exist as zymogens, and are activated by various extracellular stimuli, leading to apoptosis. One such stimulus is Fas/CD95, a member of the tumor necrosis factor receptor family, providing one means of cytotoxic T lymphocyte (CTL)-mediated cell lysis. Clinical evidence has shown that administration of cytokine leads to regression in selected patients with renal cell carcinomas (RCCs). Interferon-gamma (IFN-gamma) indicates its contribution to anti-tumor activity of immune cells. IFN-gamma elicits its effect through the transcription factor signal transducer and activator of transcription-1 (STAT-1), and through interferon regulatory factor-1 (IRF-1), one of the target genes of STAT-1. Our previous study demonstrated an increase in the susceptibility of ACHN cells, established from RCC, to Fas-mediated apoptosis by IFN-gamma, and the inhibition of this effect by the caspase-3 and -7 inhibitor, DEVD-CHO. We demonstrated the following phenomena in IFN-gamma-treated ACHN cells: 1) enhanced transcription of caspase-1, 3 and 7 mRNAs without any change in cleavage of their substrates; 2) increased cleavage DEVD (specific for caspase-3 and 7), but not YVAD (for caspase-1) or DMQD (for caspase-3), after anti-Fas/CD95 MAb treatment; 3) activation of the STAT-1 and IRF-1 pathway; and 4) partial abrogation of the IFN-gamma-induced increase in Fas-mediated apoptosis by antisense IRF-1 oligodeoxynucleotide. These results suggest that IRF-1 plays a pivotal role in the IFN-gamma-mediated-enhancement of Fas/CD95-mediated apoptosis, through regulation of DEVD-CHO-sensitive caspases, most likely caspase-7.
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PMID:Role of IRF-1 and caspase-7 in IFN-gamma enhancement of Fas-mediated apoptosis in ACHN renal cell carcinoma cells. 1258 35

We have previously demonstrated that overexpression of Cell Death Inhibiting RNA (CDIR), a portion of the 3'untranslated region (UTR) of KIAA0425, inhibits Interferon-gamma (IFN-gamma) induced apoptosis in HeLa cells (Shchors et al., J Biol Chem 2002; 277:47061-72). IFN-gamma is known to sensitize cells to killing induced by the death receptor ligands such as Fas/APO-1/CD95 and TNF-related apoptosis-inducing ligand (TRAIL/Apo-2L). Here we report that while CDIR does not alter the response of cells to Fas or TRAIL, it significantly modulates IFN-gamma-induced sensitization of HeLa cells to these death-inducing ligands. Interestingly, while CDIR abrogates the IFN-gamma-modulated sensitization to Fas, it enhances the sensitization to TRAIL. Expression of CDIR did not alter initial steps of IFN-gamma signaling including induction of Signal Transducer and Activator-1 (Stat1), caspase-1 or Interferon Regulatory Factor-1 (IRF1) transcription. In contrast, although expression of CDIR does not affect the protein level of caspase-1 or STAT1, it does significantly reduce the level of IRF1 protein. Thus, CDIR mediates IFN-gamma-induced apoptosis, at least in part, by reducing the level of the pro-apoptotic tumor suppressor gene IRF1 via a post-transcriptional mechanism. Since tumor cells are often less sensitive to Fas and more sensitive to TRAIL than normal cells, we suggest that CDIR or CDIR-like activity could contribute to such a phenotype of tumor cells.
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PMID:Cell Death Inhibiting RNA (CDIR) modulates IFN-gamma-stimulated sensitization to Fas/CD95/Apo-1 and TRAIL/Apo-2L-induced apoptosis. 1561 57

Interactions between extracellular matrix (ECM) and mammary epithelial cells are critical for mammary gland homeostasis and apoptotic signaling. Interferon regulatory factor-1 (IRF-1) is a transcriptional regulator that promotes apoptosis during mammary gland involution and p53-independent apoptosis. We have recently shown that rapid cell surface tamoxifen (Tam) signaling promotes apoptosis in normal human mammary epithelial cells that were acutely damaged by expression of human papillomavirus type-16 E6 protein (*HMEC-E6). Apoptosis was mediated by recruitment of CREB-binding protein (CBP) to the gamma-activating sequence (GAS) element of the IRF-1 promoter, induction of IRF-1 and caspase-1/-3 activation. Here, we show that growth factor-depleted, reconstituted ECM (rECM), similar to Tam, promotes apoptosis in *HMEC-E6 cells through induction of IRF-1. Apoptosis was temporally associated with recruitment of CBP to the GAS element of the IRF-1 promoter, induction of IRF-1 expression and caspase-1/-3 activation. Small interfering RNA-mediated suppression of IRF-1 protein expression in *HMEC-E6 cells blocked (1) induction of IRF-1, (2) caspase-1/-3 activation and (3) apoptosis. These observations demonstrate that IRF-1 promotes rECM-mediated apoptosis and provide evidence that both rECM and rapid Tam signaling transcriptionally activate IRF-1 through recruitment of CBP to the IRF-1 GAS promoter complex.
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PMID:Interferon regulatory factor-1 regulates reconstituted extracellular matrix (rECM)-mediated apoptosis in human mammary epithelial cells. 1701 42

Tumour necrosis factor-alpha (TNF-alpha) is a cytokine that is involved in many functions, including the inflammatory response, immunity and apoptosis. Some of the responses of TNF-alpha are mediated by caspase-1, which is involved in the production of the pro-inflammatory cytokines interleukin-1beta, interleukin-18 and interleukin-33. The molecular mechanisms involved in TNF-alpha-induced caspase-1 gene expression remain poorly defined, despite the fact that signaling by TNF-alpha has been well studied. The present study was undertaken to investigate the mechanisms involved in the induction of caspase-1 gene expression by TNF-alpha. Treatment of A549 cells with TNF-alpha resulted in an increase in caspase-1 mRNA and protein expression, which was preceded by an increase in interferon regulatory factor-1 and p73 protein levels. Caspase-1 promoter reporter was activated by the treatment of cells with TNF-alpha. Mutation of the interferon regulatory factor-1 binding site resulted in the almost complete loss of basal as well as of TNF-alpha-induced caspase-1 promoter activity. Mutation of the p53/p73 responsive site resulted in reduced TNF-alpha-induced promoter activity. Blocking of p73 function by a dominant negative mutant or by a p73-directed small hairpin RNA reduced basal as well as TNF-alpha-induced caspase-1 promoter activity. TNF-alpha-induced caspase-1 mRNA and protein levels were reduced when p73 mRNA was down-regulated by small hairpin RNA. Caspase-5 gene expression was induced by TNF-alpha, which was inhibited by the small hairpin RNA-mediated down-regulation of p73. Our results show that TNF-alpha induces p73 gene expression, which, together with interferon regulatory factor-1, plays an important role in mediating caspase-1 promoter activation by TNF-alpha.
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PMID:Tumor necrosis factor-alpha-induced caspase-1 gene expression. Role of p73. 1772 14

Mammary gland homeostasis is regulated by both endogenous and exogenous signals, creating a balance between proliferation and apoptosis. It is thought that breast cancer develops from the acquisition of multiple genetic changes. The function of tumor suppressor p53 is fequently lost in cancers; however, not all cells that lose p53 progress to become invasive cancer. We have developed a model of early mammary carcinogenesis to investigate some of the internal and external signaling pathways that target the elimination ot normal basal-type human mammary epithelial cells (HMECs) that acutely acquire p53-damage. Here, we show that both tamoxifen (Tam) and three-dimensional prepared extracellular matrix culture (3-D rECM) induce apoptosis in HMEC cells with acute loss of p53 [*p53(-) HMECs] through induction of interferon regulatory factor-1 (IRF-1). Tam and rECM signaling in *p53(-) HMECs (1) promotes the recruitment of a STAT1/ CBP complex to the IRF-1 promoter, (2) upregulates IRF-1, (3) activates caspase-1 and -3, and (4) induces apoptosis. Suppression of IRF-1 with siRNA oligos inhibited both Tam- and rECM-induced apoptosis. These observations demonstrate that IRF-1 plays a critical role in eliminating p53-damaged cells, and may play a more global role in mammary gland homeostasis.
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PMID:IRF-1 promotes apoptosis in p53-damaged basal-type human mammary epithelial cells: a model for early basal-type mammary carcinogenesis. 1849 60