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Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multiple copy tandem repeats polymers of an authentic 30-bp region of the human interferon-beta (IFN-beta) promoter between positions-91 to -62 relative to the cap site or the hexanucleotide GAAAGT derived from this region, both acted as strong constitutive regulatory elements in transfected HeLa cells. Such polymers were unresponsive to treatment with IFN-alpha despite their considerable homology with the IFN-responsive elements of other genes but were highly responsive to treatment of HeLa cells with IFN-gamma. Virus induction of HeLa cells transfected with polymers of the 30-bp region linked to a CAT gene increased the activity of the reporter gene 500- to 2,000-fold over baseline levels. Treatment with IFN-alpha prior to virus induction did not increase further CAT activity. Cotransfection of HeLa cells with the CAT gene under the control of a 12-element tandem repeat polymer of the human IFN-beta promoter and an expression vector for the IRF-1 transcriptional activator markedly increased CAT activity while cotransfection of HeLa cells with the IFN-beta construct together with an expression vector for the transcriptional regulator IRF-2 markedly decreased CAT activity relative to cells transfected with the IFN-beta polymer alone.
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PMID:Tandem repeat polymers of a critical region of the human interferon-beta promoter exhibit a marked constitutive activity and enhanced responsiveness to transcriptional regulators in transfected HeLa cells. 143 17

PRDI-BFc and PRDI-BFi are proteins that bind specifically to a regulatory element required for virus induction of the human beta interferon (IFN-beta). PRDI-BFc is a constitutive binding activity, while the PRDI-BFi binding activity is observed only after cells are treated with inducers such as virus or poly(I).poly(C) plus cycloheximide or in some cells by cycloheximide alone. In this paper we report that PRDI-BFc is interferon regulatory factor-2 (IRF-2), a known transcriptional repressor. In addition, we find that PRDI-BFi is a truncated form of IRF-2, lacking approximately 185 C-terminal amino acids. Thus, PRDI-BFi appears to be generated by inducible proteolysis. Although the affinity of PRDI-BFc/IRF-2 for the IFN-beta promoter does not appear to be affected by the removal of C-terminal amino acids, the ability of PRDI-BFi to function as a repressor in cotransfection experiments is significantly less than that of intact IRF-2. Studies have shown that IRF-2 can block the activity of the transcriptional activator IRF-1, which also binds specifically to the IFN-beta gene promoter. Thus, the inducible proteolysis of IRF-2 may be involved in the regulation of the IFN-beta gene or of other genes in which the ratio of IRF-1 to IRF-2 can affect the level of transcription.
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PMID:Inducible processing of interferon regulatory factor-2. 163 Apr 48

Interferon (IFNs), as a class of antiviral cytokines, are also known as "negative growth regulators," they inhibit the growth of a variety of normal and malignant cells. Normally, Type I IFNs (i.e. IFN-alpha, -beta) are not induced, but viruses and a number of other cytokines transiently activate the IFN genes. In order to elucidate the molecular mechanisms of cellular responses by viruses and cytokines, we have identified two nuclear factors, IRF-1 and IRF-2, both bind to the regulatory cis-elements of IFN and IFN-responsive genes. The genes encoding IRF-1 and IRF-2, have been cloned and extensively characterized. The IRF cDNA expression studies in factor-negative cells have revealed IRF-1 and IRF-2 to function as transcriptional activator and repressor, respectively. In normal cells, the IRF genes are subject to induction through stimuli such as viruses and cytokines including IFNs per se. The findings provide evidence for the presence of an elaborate network of cytokines system wherein the IRFs play a crucial role for the cytokine-mediated cellular responses.
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PMID:[Cellular responses by cytokines--gene regulation in the IFN system]. 171 1

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-beta (IFN-beta) gene is transcriptionally activated following virus infection of various cell types such as fibroblasts. In the previous studies, regulatory DNA sequences that mediate the virus-induced transcriptional activation have been identified within the 5'-flanking region (up to around -117 respect to the CAP site) of the human IFN-beta gene. The sequences contain binding sites (-100 to -61) for a transcriptional activator, IRF-1, the gene of which is also virus-inducible. In the present study, we focused on an additional cis-element, located between the IRF-1 binding sites and TATA box. Interestingly, the element coincides with the previously identified elements for the transcription factors H2TF-1 and NF kappa B. The element, when tandemly repeated, functions in activating the distal gene expression in either constitutive or virus-inducible manner depending on the cell type. The results suggest the importance of cooperation between IRF-1 and H2TF-1/NF kappa B-like factor in the maximal IFN-beta gene induction.
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PMID:Involvement of a cis-element that binds an H2TF-1/NF kappa B like factor(s) in the virus-induced interferon-beta gene expression. 256 73

IFN stimulated genes (ISGs) contain common DNA motif termed IFN consensus sequence (ICS) at their promoters that enable IFN responsiveness. Different transcription factors capable of interacting with the ICS have been described. Previously, we reported the cloning of a factor capable of binding to the ICS (ICSBP) that demonstrates similarity at DNA the binding domain with three other ICS binding factor, i.e. IRF-1, IRF-2 and ISGF3 gamma. ICSBP is expressed constitutively in hematopoietic cells and its expression is further induced by IFN-gamma. This is a negative trans-acting regulator of ISGs; however, its effect is attenuated following prolonged exposures of cells to both types of IFNs. In this communication, we show that short exposures of cells to IFNs (priming) are sufficient to alleviate ICSBP mediated repression. Further, exposure of primed cells to the synthetic dsRNA (polyl-polyC) results in total abrogation of ICSBP repression. In an attempt to unravel the molecular mechanism governing this conditional repression of ICSBP, the direct involvement of transcriptional activator IRF-1 is demonstrated. We postulate that constitutive expression of ICSBP in hematopoietic cells is mediating submaximal expression of ISGs such as MHC class I. Our data demonstrate that IRF-1 competes with ICSBP for the binding to the ISRE element, resulting in the alleviation of ICSBP repression. Thus, the magnitude of ISGs expression is a result of a fine balance between positive and negative regulators.
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PMID:IFN consensus sequence binding protein (ICSBP) is a conditional repressor of IFN inducible promoters. 752 89

Transcription of the vascular cell adhesion molecule 1 (VCAM-1) gene in endothelial cells is induced by lipopolysaccharide and the inflammatory cytokines interleukin-1 beta and tumor necrosis factor alpha (TNF-alpha). Previous studies have demonstrated that tandem binding sites for the inducible transcription factor NF-kappa B are necessary but not sufficient for full cytokine-mediated transcriptional activation. Herein, we demonstrate that full cytokine-induced accumulation of VCAM1 transcript requires protein synthesis. We report the definition of a functional regulatory element in the VCAM1 promoter interacting with the transcriptional activator interferon regulatory factor 1 (IRF-1). DNA-protein binding studies with endothelial nuclear extracts revealed that IRF-1 is cytokine inducible and binds specifically to a consensus sequence motif located 3' of the TATA element. We have identified heterodimeric p65 and p50 as the NF-kappa B species binding to the VCAM1 promoter in TNF-alpha-activated endothelial cells. Experiments with recombinant proteins showed that p50/p65 and high-mobility-group I(Y) protein cooperatively facilitated the binding of IRF-1 to the VCAM1 IRF binding site and that IRF-1 physically interacted with p50 and with high-mobility-group I(Y) protein. Transient transfection assay in endothelial cells showed that overexpressed IRF-1 resulted in superinduction of TNF-alpha-stimulated transcription. Site-directed mutations in the IRF binding element decreased TNF-alpha-induced activity and totally abolished superinduction. Cotransfection assays in P19 embryonal carcinoma cells revealed that IRF-1 synergized with p50/p65 NF-kappa B to activate the VCAM1 promoter or heterologous promoter constructs bearing isolated VCAM1 NF-kappa B and IRF binding motifs. Cytokine inducibility of VCAM1 in endothelial cells utilizes the interaction of heterodimeric p50/p65 proteins with IRF-1.
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PMID:Endothelial interferon regulatory factor 1 cooperates with NF-kappa B as a transcriptional activator of vascular cell adhesion molecule 1. 753 51

The Interferon Regulatory Factors-1 and -2 (IRF-1 and IRF-2) play a transcriptional role in the regulation of the IFN-beta gene as well as other immunoregulatory genes. IRF-1 serves as a transcriptional activator whereas IRF-2 acts as an antagonistic transcriptional repressor. IRF-1 and IRF-2 also play opposing functional roles in cell growth regulation, and are implicated as a potential antioncogene and oncogene, respectively. To analyse the relationship between DNA binding/transcriptional repression and oncogenic transformation, NIH3T3 cells expressing C-terminal deletions of IRF-2 were established and assayed for transformation by saturation density analysis, anchorage independent growth in soft agar and tumor formation in nude mice. Cells expressing an IRF-2 protein of at least 160 N-terminal amino acids were transformed in vitro and tumorigenic in vivo, thus mapping IRF-2 oncogenic activity to its DNA binding/transcriptional repression domain. Overexpression of wild-type and truncated IRF-2 proteins resulted in reduced IFN-beta mRNA levels following induction by dsRNA. However, there was no effect of IRF-2 on IFN-beta inducibility by Sendai virus infection, suggesting the involvement of multiple IFN-beta induction pathways. In DNA binding assays, recombinant IRF-2 was found to preferentially bind to the IFN-beta PRDI site compared to IRF-1. These studies indicate that the transformed phenotype resulting from overexpression of IRF-2 may be due to constitutive engagement of the IRF-E recognition site, thus preventing DNA binding and transactivation of putative tumor suppressor genes by the IRF-1 anti-oncogene.
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PMID:Transcription factor IRF-2 exerts its oncogenic phenotype through the DNA binding/transcription repression domain. 763 Jun 38

Interferon (IFN) regulatory factor 1 (IRF-1) and IRF-2 were originally identified as transcription factors involved in the regulation of the IFN system. IRF-1 functions as a transcriptional activator, while IRF-2 represses IRF-1 function. More recently, evidence has been provided that IRF-1 and IRF-2 manifest antioncogenic and oncogenic properties, respectively, and that loss of one or both of the IRF-1 alleles may be critical for the development of human hematopoietic neoplasms. Both factors show a high degree of structural similarity in their N-terminal DNA-binding domains, and previous studies suggested that IRF-1 and IRF-2 bind to similar or identical cis elements within type I IFN (IFN-alpha and -beta) and IFN-inducible genes. However, the exact recognition sequences of these two factors have not yet been determined; hence, the spectrum of the IRF-responsive genes remains unclear. In this study, we determined the DNA sequences recognized by IRF-1 and IRF-2, using a polymerase chain reaction-assisted DNA-binding site selection method. We report that sequences selected by this method and the affinities for each sequence were virtually indistinguishable between IRF-1 and IRF-2. We confirm the presence of two contiguous IRF recognition sequences within the promoter region of the IFN-beta gene and of at least one such sequence in all of the IFN-inducible genes examined. Furthermore, we report the presence of potential IRF sequences in the upstream region of several genes involved in cell growth control.
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PMID:Recognition DNA sequences of interferon regulatory factor 1 (IRF-1) and IRF-2, regulators of cell growth and the interferon system. 768 40

Interferon consensus sequence binding protein (ICSBP) is a member of the interferon regulatory factor (IRF) family of proteins that include IRF-1, IRF-2, and ISGF3gamma which share sequence similarity at the putative DNA binding domain (DBD). ICSBP is expressed exclusively in cells of the immune system and acts as a repressor of interferon consensus sequence (ICS) containing promoters that can be alleviated by interferons. In this communication, we have searched for functional domains of ICSBP by dissecting the DBD from the repression activity. The putative DBD of ICSBP (amino acids 1-121) when fused in frame to the transcriptional activation domain of the herpes simplex VP16 (ICSBP-VP16) is a very strong activator of ICS-containing promoters. In addition, ICSBP-VP16 fusion construct transfected into adenovirus (Ad) 12 transformed cells enabled cell surface expression of major histocompatibility complex class I antigens as did treatment with interferon. On the other hand, the DBD of the yeast transcriptional activator GAL4 was fused in frame to a truncated ICSBP in which the DBD was impaired resulting in a chimeric construct GAL4-ICSBP. This construct is capable of repressing promoters containing GAL4 binding sites. Thus, ICSBP contains at least two independent domains: a DBD and a transcriptional repressor domain. Furthermore, we have tested possible interactions between ICSBP and IRFs. The chimeric construct GAL4-ICSBP inhibited the stimulated effect of IRF-1 on a reporter gene, implying for a possible interaction between IRF-1 and ICSBP. Electromobility shift assays, demonstrated that ICSBP can associate with IRF-2 or IRF-1 in vitro as well as in vivo. Thus, ICSBP contains a third functional domain that enables the association with IRFs. These associations are probably important for the fine balance between positive and negative regulators involved in the interferon-mediated signal transduction pathways in cells of the immune system.
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PMID:Functional domain analysis of interferon consensus sequence binding protein (ICSBP) and its association with interferon regulatory factors. 776


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