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

The proto-oncogene C-jun acts as a transcriptional activator or repressor for numerous cellular genes, and the overexpression of these genes may cause malignant transformation. JunB inhibits c-jun's transforming activities. We investigated the expression of jun genes in renal cell cancer (RCC) and their regulation by cytokines and transforming growth factor beta 1 (TGF-b1). The constitutive expression of c-jun was detected in 39 of 43 fresh frozen RCC, 5 of 10 normal kidneys, and the expression of junB detected in 28 of 34 RCC, 5 of 6 normal kidneys. C-jun was also found expressed in all 10 RCC tumor lines examined and junB was expressed at low levels in 6 of 10 renal tumor lines. TGF-b1 and tumor necrosis factor alpha (TNF-a) have been shown to alter the expression of jun genes in other tissue types. Additionally, TGF-b1, TNF-a, and gamma interferon (g-IFN) were shown to inhibit the growth of RCC. We found that TGF-b1 highly augmented the expression of junB (mean of 34 folds, p less than .05), but did not significantly alter the expression of c-jun, the transforming gene. In contrast, TNF-a significantly enhanced the expression of both c-jun (mean fold enhancement of 2.1, p less than .05) and junB (2.2 folds, p less than .05). Interleukin-2 (IL-2), interleukin-4 (IL-4) and g-IFN did not significantly alter jun expression. The findings presented suggest that c-jun may have a role in inducing malignant transformation in RCC and a novel mechanism by which TGF-b1 may exert its anti-tumor effects, via the activation of junB. Additionally, although TGF-b1, TNF-a, and g-IFN all have anti-proliferative actions on RCC in vitro, they were found to have different effects in altering jun expressions.
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PMID:The expression of C-jun and junB mRNA in renal cell cancer and in vitro regulation by transforming growth factor beta 1 and tumor necrosis factor alpha 1. 140 66

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

The interferon-alpha (IFN-alpha)-stimulated gene factor 3 (ISGF3), a transcriptional activator, contains three proteins, termed ISGF3 alpha proteins, that reside in the cell cytoplasm until they are activated in response to IFN-alpha. Treatment of cells with IFN-alpha caused these three proteins to be phosphorylated on tyrosine and to translocate to the cell nucleus where they stimulate transcription through binding to IFN-alpha-stimulated response elements in DNA. IFN-gamma, which activates transcription through a different receptor and different DNA binding sites, also caused tyrosine phosphorylation of one of these proteins. The ISGF3 alpha proteins may be substrates for one or more kinases activated by ligand binding to the cell surface and may link occupation of a specific polypeptide receptor with activation of transcription of a set of specific genes.
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PMID:Interferon-dependent tyrosine phosphorylation of a latent cytoplasmic transcription factor. 138 85

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

When treated with IFN-alpha, NIH-3T3 cells express after a few hours high levels of the mouse 202 gene mRNA. This activation takes place at the transcriptional level as shown by nuclear "run on" assay. For this purpose a fragment of 806 base-pairs (the b fragment), spanning the 5'-flanking region of the 202 gene, was linked to the reporter CAT gene and transiently transfected into mouse NIH 3T3. The data suggest that the b fragment is sufficient to confer transcriptional inducibility upon IFN stimulation and can account in large part for the response of the 202 gene. Binding assays, using a 40-bp probe derived from the IFN-stimulated response element (ISRE) comprised in the b fragment, demonstrated the presence of two DNA-binding proteins. One of these, defined as complex A, was inducible upon IFN treatment, whereas the other, defined as complex B, was constitutively present regardless of IFN treatment. The IFN-alpha-induced complex A appears to have the necessary characteristics to be the transcriptional activator of the 202 gene: it requires the same nucleotides for binding as are required for IFN-dependent gene activation and is dependent on IFN-alpha treatment.
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PMID:Characterization of the nuclear factors involved in 202 gene induction by IFN-alpha in NIH-3T3 cells. 176 55

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

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

Induction by gamma interferon (IFN-gamma) of the gene encoding the human high-affinity Fc gamma receptor (Fc gamma R1) in myeloid cells requires an IFN-gamma response region (GRR) and a myeloid cell-activating transcription element (MATE). GRR and MATE interact with factors to form, respectively, an IFN-gamma-activating complex (GIRE-BP), depending on the phosphorylation of the 91-kDa protein (subunit of ISGF3), and a cell-type-specific complex (MATE-BP). Although GIRE-BP is detected in cells of different origins after IFN-gamma treatment, the presence of MATE-BP was found to be restricted to B- and myeloid cell lines. Sequence analysis of a cDNA encoding a polypeptide recognizing specifically the MATE motif led to the identification of this product as the proto-oncogene PU.1/Spi-1, a transcriptional activator expressed in myeloid and B cells. Expression of this factor in nonhematopoietic cells allowed IFN-gamma-induced expression of a reporter gene under control of the GRR and MATE sequences. The presence of these motifs in other gene promoters indicates that the binding of PU.1/Spi-1 and IFN regulatory proteins to their respective motifs could be part of a general mechanism leading to cell-type-restricted and IFN-induced gene expression.
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PMID:Involvement of the transcription factor PU.1/Spi-1 in myeloid cell-restricted expression of an interferon-inducible gene encoding the human high-affinity Fc gamma receptor. 803 86

The correlation between virus induced NF-kappa B DNA binding activity and interferon gene expression was examined in the myelomonoblastic PLB-985 cell line. Previous studies have shown that chronic HIV-1 infection of PLB-985 cells (PLB-IIIB) leads to the selection of cells with a more differentiated monocytic phenotype and with constitutive NF-kappa B DNA-binding activity. In this report we demonstrate that the kinetics of HIV-1 and Sendai virus infection of PLB-985 cells directly correlates with induction of NF-kappa B DNA binding activity. Based on UV cross-linking and immunoprecipitation analysis, p50, the strong transcriptional activator p65 and c-Rel represent the major constituents of this NF-kappa B DNA-binding activity. We also demonstrate an alteration in the kinetics of type I IFN gene transcription following secondary Sendai virus infection of PLB-IIIB cells compared to PLB-985. The results of our studies suggest that HIV infected individuals may respond differently to secondary viral or bacterial infections by augmenting the synthesis of NF-kappa B regulated immune response modifiers, which could alter the onset or progression of AIDS.
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PMID:Virus induction of NF-kappa B/Rel proteins and type I interferon gene expression in myelomonoblastic cells. 815 86

The 5' terminal flanking region of the interferon-inducible gene, 202, contains an interferon-stimulable response element (ISRE), called a GA box, that confers inducibility by interferon(IFN)-alpha, but not by IFN-gamma, on a reporter gene, such as the chloramphenicol acetyltransferase (CAT). Nuclear extracts from L1210 murine leukemia cells, stimulated for various periods of time with IFN-alpha, were mixed with 32P-labeled GA box and analyzed for the presence of retarded complexes in electrophoretic-mobility-shift assays. In addition to a few constitutive retarded complexes, an inducible GA box-binding activity (GAbf-1) appeared after 5 min, peaked at about 2 h, and was still abundant 12 h after IFN-alpha treatment. In the cytoplasmic fraction GAbf-1 was not detectable before 30 min, continued to increase up to 2 h, but had disappeared within 12 h. GAbf-1 activity was not observed in nuclear extracts treated with IFN-gamma, and was not inhibited by prior treatment with the protein-synthesis inhibitor cycloheximide. When the binding properties of GAbf-1 were compared with those of ISGF-3, the primary transcriptional activator for IFN-alpha-induced genes, a different pattern of retarded complexes was observed. Moreover, as observed by immunoblotting analysis, nuclear extracts from IFN-alpha-treated L1210 cells did not contain the p91/84 subunit of the ISGF3, the best characterized nuclear complex activated by IFN-alpha. Altogether these results indicate that GAbf-1 may be a novel transcription factor exploited by IFN-alpha to activate the 202 inducible gene in murine pre-B leukemia cells.
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PMID:Characterization of nuclear factors involved in 202 gene induction by interferon-alpha in murine leukemia cells. 817 52


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