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)

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.
 ...
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

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.
 ...
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.
 ...
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) and IRF-2 are structurally similar DNA-binding factors which were originally identified as regulators of the type I interferon (IFN) system; the former functions as a transcriptional activator, and the latter represses IRF-1 function by competing for the same cis elements. More recent studies have revealed new roles of the two factors in the regulation of cell growth; IRF-1 and IRF-2 manifest antioncogenic and oncogenic activities, respectively. In this study, we determined the structures and chromosomal locations of the human IRF-1 and IRF-2 genes and further characterized the promoters of the respective genes. Comparison of exon-intron organization of the two genes revealed a common evolutionary structure, notably within the exons encoding the N-terminal portions of the two factors. We confirmed the chromosomal mapping of the human IRF-1 gene to 5q31.1 and newly assigned the IRF-2 gene to 4q35.1, using fluorescence in situ hybridization. The 5' regulatory regions of both genes contain highly GC-rich sequences and consensus binding sequences for several known transcription factors, including NF-kappa B. Interestingly, one IRF binding site was found within the IRF-2 promoter, and expression of the IRF-2 gene was affected by both transient and stable IRF-1 expression. In addition, one potential IFN-gamma-activated sequence was found within the IRF-1 promoter. Thus, these results may shed light on the complex gene network involved in regulation of the IFN system.
 ...
PMID:Structure and regulation of the human interferon regulatory factor 1 (IRF-1) and IRF-2 genes: implications for a gene network in the interferon system. 750 7

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.
 ...
PMID:IFN consensus sequence binding protein (ICSBP) is a conditional repressor of IFN inducible promoters. 752 89

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.
 ...
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.
 ...
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.
 ...
PMID:Functional domain analysis of interferon consensus sequence binding protein (ICSBP) and its association with interferon regulatory factors. 776

The transcriptional activator interferon regulatory factor 1 (IRF-1) and its antagonistic repressor IRF-2 are regulators of the interferon (IFN) system and of cell growth. Here we report that embryonic fibroblasts (EFs) from mice with a null mutation in the IRF-1 gene (IRF-1-/- mice) can be transformed by expression of an activated c-Ha-ras oncogene. This property is not observed in EFs from wild-type or IRF-2-/- mice but is still observed in EFs from mice deficient in both genes. The transformed phenotype of ras-expressing IRF-1-/- EFs could be suppressed by the expression of the IRF-1 cDNA. Thus, IRF-1 functions as a tumor suppressor. Furthermore, expression of the c-Ha-ras oncogene causes wild-type but not IRF-1-/- EFs to undergo apoptosis when combined with a block to cell proliferation or treated by anticancer drugs or ionizing radiation. Hence, IRF-1 may be a critical determinant of oncogene-induced cell transformation or apoptosis.
 ...
PMID:Cellular commitment to oncogene-induced transformation or apoptosis is dependent on the transcription factor IRF-1. 800 72

The mechanisms underlying interferon (IFN)-induced antiviral states are not well understood. Interferon regulatory factor-1 (IRF-1) is an IFN-inducible transcriptional activator, whereas IRF-2 suppresses IRF-1 action. The inhibition of encephalomyocarditis virus (EMCV) replication by IFN-alpha and especially by IFN-gamma was impaired in cells from mice with a null mutation in the IRF-1 gene (IRF-1-/- mice). The IRF-1-/- mice were less resistant than normal mice to EMCV infection, as revealed by accelerated mortality and a larger virus titer in target organs. The absence of IRF-1 did not clearly affect replication of two other types of viruses. Thus, IRF-1 is necessary for the antiviral action of IFNs against some viruses, but IFNs activate multiple activation pathways through diverse target genes to induce the antiviral state.
 ...
PMID:Involvement of the IRF-1 transcription factor in antiviral responses to interferons. 800 22


1 2 3 Next >>