Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The transcriptional activator IRF-1 and its antagonistic repressor IRF-2 are regulators of the interferon (IFN) system and of cell growth. Overexpression of IRF-2 leads to transformation of NIH3T3 cells, and the concomitant overexpression of IRF-1 reverts this transformed phenotype. Here we report that c-myc- or fosB-transformed rat embryonic fibroblast cells can be reverted by the introduction of the IRF-1 gene. Thus, the anti-oncogenic function of IRF-1 is not limited to only IRF-2 overexpressing cells, suggesting the broad role of IRF-1 as a tumor suppressor.
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PMID:Suppression of c-myc or fosB-induced cell transformation by the transcription factor IRF-1. 806 14

Interferon regulatory factor 1 (IRF-1), a transcriptional activator, and its antagonistic repressor, IRF-2, were originally identified as regulators of the type I interferon (IFN) system. We have generated mice deficient in either IRF-1 or IRF-2 by gene targeting in embryonic stem cells. IRF-1-deficient fibroblasts lacked the normally observed type I IFN induction by poly(I):poly(C), while they induced type I IFN to similar levels as the wild type following Newcastle disease virus (NDV) infection. In contrast, IRF-2-deficient fibroblasts showed up-regulated type I IFN induction by NDV infection. A profound reduction of TCR alpha beta+CD4-CD8+ T cells in IRF-1-deficient mice, with a thymocyte developmental defect, reveals a critical role for IRF-1 in T cell development. IRF-2-deficient mice exhibited bone marrow suppression of hematopoiesis and B lymphopoiesis and mortality following lymphocytic choriomeningitis virus infection.
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PMID:Targeted disruption of IRF-1 or IRF-2 results in abnormal type I IFN gene induction and aberrant lymphocyte development. 840 3

Interferon regulatory factor-1 (IRF-1), a transcriptional activator, and IRF-2, its antagonistic repressor, have been identified as regulators of type I interferon and interferon-inducible genes. The IRF-1 gene is itself interferon-inducible and hence may be one of the target genes critical for interferon action. When the IRF-2 gene was overexpressed in NIH 3T3 cells, the cells became transformed and displayed enhanced tumorigenicity in nude mice. This transformed phenotype was reversed by concomitant overexpression of the IRF-1 gene. Thus, restrained cell growth depends on a balance between these two mutually antagonistic transcription factors.
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PMID:Anti-oncogenic and oncogenic potentials of interferon regulatory factors-1 and -2. 843 57

The transcriptional activator IFN regulatory factor 1 (IRF-1) and its antagonistic repressor IRF-2 are regulators of the IFN system. IRF-1 also manifests tumor suppressive activity, and its inactivation could contribute to the development of human hematopoietic malignancies. Here, we report the identification of the lysyl oxidase gene as a target gene of IRF-1. An IRF response element was identified in the lysyl oxidase gene promoter. We also demonstrate that the transformed phenotype of ras-expressing embryonic fibroblasts with a null mutation in the IRF-1 allele could be suppressed by the expression of the lysyl oxidase cDNA, implicating its potential role in tumor suppression. Thus, the regulation of the lysyl oxidase gene by IRF-1 could contribute to the multistep process of malignant transformation.
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PMID:Identification of the lysyl oxidase gene as target of the antioncogenic transcription factor, IRF-1, and its possible role in tumor suppression. 862 21

Interferon regulatory factors (IRFs) bind to the interferon-stimulated response element (ISRE) and regulate interferon- and virus-mediated gene expression. IRF-1 acts as a transcriptional activator, while IRF-2 acts as a repressor. Here we show that IRF-1 and IRF-2 bind to both cellular TFIIB, a component of the basal transcription machinery, and recombinant TFIIB (rTFIIB) and that this protein-protein interaction facilitates binding of IRFs to the ISRE. A functional interaction between TFIIB and IRF was assessed by a newly established in vitro transcription assay in which recombinant IRF-1 (rIRF-1) stimulated transcription specifically from an ISRE-containing template. With this assay we show that rIRF-1 and rTFIIB cooperatively enhance the ISRE promoter in vitro. We found that the activity of an ISRE-containing promoter was cooperatively enhanced upon cotransfection of TFIIB and IRF-1 cDNAs into P19 embryonal carcinoma cells, further demonstrating functional interactions in vivo. The cooperative enhancement by TFIIB and IRF-1 was independent of the TATA sequence in the ISRE promoter but dependent on the initiator sequence (Inr) and was abolished when P19 cells were induced to differentiate by retinoic acid treatment. In contrast, cotransfection of TFIIB and IRF-1 into NIH 3T3 cells resulted in a dose-dependent repression of promoter activation which occurred in a TATA-dependent manner. Our results indicate the presence of a cell type-specific factor that mediates the functional interaction between IRFs and TFIIB and that acts in conjunction with the requirement of TATA and Inr for promoter activation.
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PMID:Interferon regulatory factors and TFIIB cooperatively regulate interferon-responsive promoter activity in vivo and in vitro. 888 61

Replication of the Epstein-Barr virus (EBV) genome within latently infected cells is dependent on the EBV EBNA-1 protein. The objective of this study was to identify transcriptional regulatory proteins that mediate EBNA-1 expression via the viral promoter Qp, which is active in EBV-associated tumors such as Burkitt lymphoma and nasopharyngeal carcinoma. Results of a yeast one-hybrid screen suggested that a subset of the interferon regulatory factor (IRF) family may regulate EBNA-1 transcription by targeting an essential cis-regulatory element of Qp, QRE-2. Further investigation indicated that the transcriptional activator IRF-1 and the closely related IRF-2, a repressor of interferon-induced gene expression, are both capable of activating Qp. However, the major QRE-2-specific binding activity detected within extracts of Burkitt lymphoma cells was attributed to IRF-2, suggesting that interferon-independent activation of Qp is largely mediated by IRF-2 in these cells. We observed no effect of gamma interferon on Qp activity in transfection assays, whereas we observed a moderate but significant repression of Qp activity in response to alpha interferon, possibly mediated by either the interferon consensus sequence binding protein or IRF-7, a novel alpha interferon-inducible factor identified in this study. Since expression of IRF-1 and IRF-2 is increased in response to interferons, the Qp activity observed in the presence of interferon likely represented an equilibrium between IRF factors that activate and those that repress gene expression in response to interferon. Thus, by usurping both IRF-1 and its transcriptional antagonist IRF-2 to activate Qp, EBV has evolved not only a mechanism to constitutively express EBNA-1 but also one which may sustain EBNA-1 expression in the face of the antiviral effects of interferon.
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PMID:Interferon-independent and -induced regulation of Epstein-Barr virus EBNA-1 gene transcription in Burkitt lymphoma. 926 15

Complex cellular responses are often coordinated by a genetic regulatory network in which a given transcription factor controls the expression of a diverse set of target genes. Interferon regulatory factor (IRF)-1 and IRF-2 have originally been identified as a transcriptional activator and repressor, respectively, of the interferon-beta (IFN-beta) as well as of IFN-inducible genes. However, these factors have since been shown to modulate not only the cellular response to IFNs, but also cell growth, susceptibility to transformation by oncogenes, induction of apoptosis, and development of the T cell immune response. Furthermore, the evidence suggests that deletion and/or inactivation of the IRF-1 gene may be a critical step in the development of some human hematopoietic neoplasms. Subsequently, these factors have been shown to constitute a family of transcription factors, termed the IRF-family. Recent studies indicate that other IRF family members also involve the regulation of the IFN system and cell transformation. The IRF-family may be examples of transcription factors which can selectively modulate several sets of genes depending on the cell type and/or nature of the cellular stimuli, so as to evoke host defense mechanisms against infection and oncogenesis.
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PMID:The role of interferon regulatory factors in the interferon system and cell growth control. 986 86

Interferon-inducible expression of major histocompatibility class I genes has previously been found to be quantitatively and functionally deficient in neurons compared to other somatic cells or other neural cell types including astrocytes. This deficiency is a key component of neuronal immunoprivilege during viral infections of the CNS. To the contrary, in the present study, induction of functional antiviral state by IFN-beta in neurons compared to astrocytes was found to be highly efficient with respect to both viral replication and protection from cytopathic effects. A candidate antiviral state gene found to be efficiently induced in neurons by IFN-beta was the 2'-5'-oligoadenylate synthetase (OAS) gene. Unlike MHC class I genes, induction of OAS was comparable in neurons and astrocytes indicating differential expression in these neural cell types. Analysis of OAS gene promoter activity indicated that induction of the OAS gene by IFN-beta was dependent on a region containing the interferon stimulated responsive element (ISRE). In contrast, a construct containing the MHC class I-ISRE responsible for induction by IFN-beta in astrocytes was not responsive to IFN-beta in neurons. Therefore, transcription factor binding to the OAS- and MHC-ISREs was analyzed. While the OAS and MHC Class I site bound equal amounts of the transcriptional repressor IRF-2, the OAS-ISRE preferentially interacted with the transcriptional activator ISGF3 in response to IFN-beta. Further, unlike neurons, upregulation of MHC class I genes in astrocytes was related to binding of IRF-1 instead of IRF-2 to the MHC-ISRE. It is proposed that selective activation of anti-viral state genes compared to MHC class I genes by IFN-beta in neurons is mediated by preferential induction and binding of ISGF3 to anti-viral state gene ISREs but not the MHC-ISRE.
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PMID:A mechanism for selective induction of 2'-5' oligoadenylate synthetase, anti-viral state, but not MHC class I genes by interferon-beta in neurons. 1032 80

Type I interferon (IFN) receptor consists of two chains (Hu-IFN-alphaR1 and Hu-IFN-alphaR2), and Hu-IFN-alphaR2 takes a soluble (Hu-IFN-alphaR2a), short (Hu-IFN-alphaR2b), or long (Hu-IFN-alphaR2c) form. We examined the expression of type I IFN receptor, the growth-suppression effect of IFN-alpha, and their relationship in 13 liver cancer cell lines. With reverse-transcription polymerase chain reaction (RT-PCR) analysis, the expressions of Hu-IFN-alphaR1, Hu-IFN-alphaR2a, and Hu-IFN-alphaR2c were confirmed in all cell lines, and that of Hu-IFN-alphaR2b in 12 cell lines. All cell lines expressed mRNAs of a transcriptional activator, interferon regulatory factor (IRF)-1, and its antagonistic repressor (IRF-2). Flow cytometry revealed weak expression of Hu-IFN-alphaR2 on the cell surface in 12 cell lines. The soluble-form protein of Hu-IFN-alphaR2 was detected at varying levels in culture supernatants of all cell lines with enzyme-linked immunosorbent assay (ELISA). Cell proliferation was suppressed in proportion to the dose of human natural IFN-alpha at 96 hours of culture, but it was not clearly related to the expression of Hu-IFN-alphaR2 protein on the cell surface. Investigations on the morphology, DNA, and cell cycle presented four growth suppression patterns as a result of IFN-alpha: 1) induction of apoptosis and blockage of cell cycle at the S phase (9 cell lines); 2) blockage at the S phase (2 cell lines); 3) induction of apoptosis and blockage at the G2/M phase (1 cell line); and 4) blockage at the G1 phase (1 cell line). There was no evidence showing that changes in the expressions of Bcl-2, Bcl-xL, Bak, and Bax lead directly to IFN-alpha-mediated apoptosis. Our findings demonstrated that IFN-alpha would express growth-suppression effects at varying degrees by inducing inhibition of cell-cycle progression with or without apoptosis, regardless of the expression level of Hu-IFN-alphaR2 protein on the cell surface.
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PMID:Interferon alfa receptor expression and growth inhibition by interferon alfa in human liver cancer cell lines. 1034 12

We investigated the role of interferon (IFN) regulatory factor-2 (IRF-2) as an oncoprotein in vivo, opposing endogenous IFN-gamma suppression of tumor growth. Using syngeneic IFN-gamma knockout mice, we show that endogenous IFN-gamma slows growth of the mouse melanoma cell line B16-F10 in immunocompetent mice, suggesting that tumor cell resistance to IFN-gamma may lead to greater tumorigenicity. IRF-2 is a nuclear transcription factor induced by IFN-gamma that represses numerous IFN-inducible genes, including genes that regulate cell growth, in opposition to the transcriptional activator IRF-1. B16-F10 has a marked growth inhibitory response to IFN-gamma in vitro and has very little IRF-2 induction compared with other murine tumor cell lines. We engineered B16-F10 cells to stably overexpress murine IRF-2. In vitro, these transfected cells showed a marked resistance to the growth-inhibitory effect of IFN-gamma. In normal mice the IRF-2-transfected cells grew much faster than control tumors. In syngeneic IFN-gamma knockout mice, control cells grew at a rate similar to that of IRF-2-transfected cells, implicating resistance to endogenous IFN-gamma as playing the major role in enhanced growth of IRF-2-transfected tumors in intact mice. These experiments demonstrate that (1) IRF-2 enhances B16 melanoma growth and increases resistance to IFN-gamma in vitro, and (2) IRF-2 opposes the growth suppression mediated by endogenous IFN-gamma in vivo.
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PMID:Enhancing in vivo tumorigenicity of B16 melanoma by overexpressing interferon regulatory factor-2: resistance to endogenous IFN-gamma. 1045 42


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