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

Expression of the Type I IFN (i.e., IFN-alpha s and IFN-beta) genes is efficiently induced by viruses at the transcriptional level. This induction is mediated by at least two types of positive regulatory elements located in the human IFN-beta gene promoter: (1) the repeated elements which bind both the transcriptional activator IRF-1 and the repressor IRF-2 (IRF-elements; IRF-Es), and (2) the kappa B element (kappa B-E), which binds NF kappa B and is located between the IRF-Es and the TATA box. In this study we demonstrate that a promoter containing synthetic IRF-E, which displays high affinity for the IRFs can be efficiently activated by Newcastle disease virus (NDV). In contrast, such activation was either very weak or nil when cells were treated by IFN-beta or tumor necrosis factor-alpha (TNF-alpha), despite the fact they both efficiently induce de novo synthesis of the short-lived IRF-1 in L929 cells. In fact, efficient activation of the IRF-E apparently requires an event in addition to de novo IRF-1 induction, which can be elicited by NDV even in the presence of protein synthesis inhibitor, cycloheximide. Moreover, efficient activation of the IRF-E by NDV is specifically inhibited by the protein kinase inhibitor, Staurosporin. Hence our results suggest the importance of IRF-1 synthesis and post-translational modification event(s), possibly phosphorylation for the efficient activation of IRF-Es, which are otherwise under negative regulation by IRF-2.
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PMID:Activation of IFN-beta element by IRF-1 requires a posttranslational event in addition to IRF-1 synthesis. 188 66

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

Viperin is an antiviral protein whose expression is highly upregulated during viral infections via IFN-dependent and/or IFN-independent pathways. We examined the molecular alterations induced by the transcriptional activator IFN regulatory factor (IRF)-1 and found viperin to be among the group of IRF-1 regulated genes. From these data, it was not possible to distinguish genes that are primary targets of IRF-1 and those that are targets of IRF-1-induced proteins, like IFN-beta. In this study, we show that IRF-1 directly binds to the murine viperin promoter to the two proximal IRF elements and thereby induces viperin expression. Infection studies with embryonal fibroblasts from different gene knock-out mice demonstrate that IRF-1 is essential, whereas the type I IFN system is dispensable for vesicular stomatitis virus induced viperin gene transcription. Further, IRF-1, but not IFN type I, mediates the induction of viperin transcription after IFN-gamma treatment. In contrast, IRF-1 is not required for IFN-independent viperin induction by Newcastle disease virus infection and by infection with a vesicular stomatitis virus mutant that is unable to block IFN expression and secretion. We conclude that the IRF-1 mediated type I IFN independent mechanism of enhanced viperin expression provides a redundant mechanism to protect cells from viral infections. This mechanism becomes important when viruses evade innate immunity by antagonizing the induction and function of the IFN system.
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PMID:IFN regulatory factor-1 bypasses IFN-mediated antiviral effects through viperin gene induction. 2030 29

Nuclear localization of paramyxovirus proteins is crucial for virus life cycle, including the regulation of viral replication and the evasion of host immunity. We previously showed that a recombinant Newcastle disease virus (NDV) with nuclear localization signal mutation in the matrix (M) protein results in a pathotype change and attenuates viral pathogenicity in chickens. However, little is known about the nuclear localization functions of NDV M protein. In this study, the potential functions of the M protein in the nucleus were investigated. We first demonstrate that nuclear localization of the M protein could not only promote the cytopathogenicity of NDV but also increase viral RNA synthesis and transcription efficiency in DF-1 cells. Using microarray analysis, we found that nuclear localization of the M protein might inhibit host cell transcription, represented by numerous up-regulating genes associated with transcriptional repressor activity and down-regulating genes associated with transcriptional activator activity. The role of representative up-regulated gene prospero homeobox 1 (PROX1) and down-regulated gene aryl hydrocarbon receptor (AHR) in the replication of NDV was then evaluated. The results show that siRNA-mediated knockdown of PROX1 or AHR significantly reduced or increased the viral RNA synthesis and viral replication, respectively, demonstrating the important roles of the expression changes of these genes in NDV replication. Together, our findings demonstrate for the first time that nuclear localization of NDV M protein promotes virus replication by affecting viral RNA synthesis and transcription and inhibiting host cell transcription, improving our understanding of the molecular mechanism of NDV replication and pathogenesis.
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PMID:Nuclear localization of Newcastle disease virus matrix protein promotes virus replication by affecting viral RNA synthesis and transcription and inhibiting host cell transcription. 3089 3