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

Many members of the cytokine receptor superfamily initiate intracellular signaling by activating members of the Jak family of tyrosine kinases. Activation of the same Jaks by multiple cytokines raises the question of how these cytokines activate distinct intracellular signaling pathways. Selection of particular substrates--the transcriptional activator Stat3 and protein tyrosine phosphatase PTP1D--that characterize responses to the ciliary neurotrophic factor-interleukin-6 cytokine family depended not on which Jak was activated, but was instead determined by specific tyrosine-based motifs in the receptor components--gp130 and LIFR--shared by these cytokines. Further, these tyrosine-based motifs were modular, because addition of a Stat3-specifying motif to another cytokine receptor, that for erythropoietin, caused it to activate Stat3 in a ligand-dependent fashion.
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PMID:Choice of STATs and other substrates specified by modular tyrosine-based motifs in cytokine receptors. 787 33

Constitutive up-regulation of interleukin-6 (IL-6) gene expression is observed in many neoplastic cell lines. The contribution of mutations in p53 to the up-regulation of the IL-6 promoter was evaluated in transient transfection experiments. In HeLa cells, wild-type (wt) human or murine p53 preferentially repressed the IL-6 promoter. The p53 mutants Val-135 and Phe-132 up-regulated IL-6 promoter activity in these cells at both 32.5 and 37 degrees C. The temperature-sensitive Val-135 mutant was not only not inhibitory or "wt-like" at the lower temperature, but had gained a transcriptional activator phenotype which was temperature-independent in HeLa cells. The functional DNA target for transcriptional modulation of the IL-6 promoter by p53 species included the multiple cytokine- and second messenger-response element (-173 to -145); point mutations in the transcription factor C/EBP beta-binding site within the second messenger-response element largely blocked the ability of p53 mutants Val-135 and Phe-132 to up-regulate this promoter. The up-regulation of IL-6 promoter constructs by co-transfection into HeLa cells of a C/EBP beta constitutive expression vector was blocked in a dominant negative manner by wt p53. In contrast, the p53 mutants Val-135 and Phe-132 further enhanced C/EBP beta-mediated up-regulation of IL-6 promoter constructs. The modulation of C/EBP beta function by p53 species provides a basis for the involvement of p53 not only in the regulation of cytokine synthesis but also in the altered responsiveness of tumor cells to cytokines.
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PMID:Modulation of the human interleukin-6 promoter (IL-6) and transcription factor C/EBP beta (NF-IL6) activity by p53 species. 832 85

We examined the biological function of a nonstructural regulatory protein, NS1, of human parvovirus B19. Because of the cytotoxic activity of NS1, human hematopoietic cell lines, K562, Raji, and THP-1, were established as transfectants which produce the viral NS1 protein upon induction by using bacterial lactose repressor/operator system. NS1 was significantly produced in the three transfectant cells in an inducer dose- and time-dependent manner. Surprisingly, these three transfectants secreted an inflammatory cytokine, interleukin-6 (IL-6), in response to induction. However, no production of other related cytokines, IL-1beta, IL-8, or tumor necrosis factor alpha, was seen. Moreover, NS1-primed IL-6 induction was transiently demonstrated in primary human endothelial cells. Analysis with luciferase reporter plasmids carrying IL-6 promoter mutant fragments demonstrated that NS1 effect is mediated by a NF-kappaB binding site in the IL-6 promoter region, strongly implying that NS1 functions as a trans-acting transcriptional activator on the IL-6 promoter. Our novel finding, IL-6 induction by NS1, supports the possible relationship between parvovirus B19 infection and polyclonal activation of B cells in rheumatoid arthritis and indicates that NS1 protein may play a significant role in the pathogenesis of some B19-associated diseases by modulating the expression of host cellular genes.
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PMID:A cytotoxic nonstructural protein, NS1, of human parvovirus B19 induces activation of interleukin-6 gene expression. 897 Sep 71

Interleukin-6 (IL-6) is a pleiotropic cytokine playing important roles in immunity, hemopoiesis and inflammation. IL-6 signalling is known to involve the activation of two independent transcription factors: Stat3 (through phosphorylation by Jak kinases) and C/EBP beta (through activation of the ras pathway). In addition, C/EBP beta is believed to act as a transcriptional activator of the IL-6 gene itself. Making use of IL-6-deficient mice, we have recently demonstrated that IL-6 is essential for the induction of acute phase mRNAs in the liver upon localized tissue damage, but not upon systemically induced inflammation. Here we show that the defective mRNA induction is paralleled by a defective activation of Stat3, thus establishing a direct relationship between IL-6 function, Stat3 activation and acute phase genes induction. On the other hand, making use of C/EBP beta-deficient mice, we show that the induction of IL-6 by a variety of stimuli does not require C/EBP beta activity. In contrast to the predicted activating role of C/EBP beta, IL-6 levels are increased in the C/EBP beta-deficient mice, suggesting that C/EBP beta may act as a down-modulator of the IL-6 gene. Through the generation of C/EBP beta, IL-6 double mutant mice we show that IL-6 hyperproduction is responsible for the development of the Castleman's like lymphoproliferative disease described in the C/EBP beta-deficient mice, since the disorder is completely blocked by inactivating the IL-6 gene.
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PMID:Interleukin-6 and CAAT/enhancer binding protein beta-deficient mice act as tools to dissect the IL-6 signalling pathway and IL-6 regulation. 944 86

Transcription factors belonging to the CCAAT-enhancer binding protein (C/EBP) family have been implicated in the regulation of gene expression during growth, differentiation, apoptosis, and inflammation. Autoregulation is relatively common in the modulation of C/EBP gene expression and, for the human and murine C/EBPalpha, it is known that species-specific autoregulatory mechanisms operate. It is therefore essential to investigate the autoregulation of additional C/EBP genes from a wider range of different species to gauge the degree of commonality, or otherwise, which exists. As an important step towards this goal, we report here the cloning and the characterisation of the ovine C/EBPdelta gene (ovC/EBPdelta) and analysis of its promoter region. Transient transfection assays reveal that ovC/EBPdelta acts as a transcriptional activator. Although several motifs that are characteristic of C/EBPdelta genes are conserved in the ovine sequence, including the basic region, leucine zipper, and activation domains, two regions have been identified that are specifically absent in the ovine and bovine homologues. The ovC/EBPdelta promoter is active in both the hepatoma Hep3B and the mammary epithelial HC11 cell lines, induced by the cytokine interleukin-6 and autoregulated by mechanisms that are potentially different from those described for the rat promoter. These results suggest that, in common with C/EBPalpha, the C/EBPdelta genes may also be subject to autoregulation by distinct species-specific mechanisms.
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PMID:The ovine CCAAT-enhancer binding protein delta gene: cloning, characterization, and species-specific autoregulation. 1079

Human herpesvirus 8 (HHV-8; Kaposi's sarcoma-associated herpesvirus is linked to Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD), all of which are viewed as cytokine-driven malignancies. In particular, interleukin-6 (IL-6) has been found to promote the growth and proliferation of cells from KS and PEL. HHV-8 encodes a homologue of IL-6 (viral IL-6 [vIL-6]), which functions similarly to the cellular IL-6. Therefore, vIL-6 has been proposed to play an important role in tumor progression. Several groups have reported that vIL-6 is expressed from the HHV-8 genome at higher levels in PEL and MCD lesions than in KS lesions. However, it is not clear how vIL-6 expression is regulated. We characterized the transcription at the vIL-6 gene locus by Northern blot analysis and, in contrast to previous reports, we observed two distinct transcripts from induced PEL cell lines. This observation was confirmed by primer extension, as well as 5' and 3' rapid amplification of cDNA ends. Two transcription initiation sites and putative TATA boxes were mapped. A luciferase reporter system was used to show that each of the two putative TATA boxes contributed to vIL-6 promoter activity. Since virally encoded transcriptional activator Rta potently activates the viral lytic gene expression cascade, we examined the role of Rta in controlling vIL-6 gene expression and found that Rta activated the vIL-6 promoter. The Rta-responsive element was further mapped through a series of deletion constructs. Electrophoretic mobility shift assays demonstrated that Rta binds directly to the vIL-6 Rta-responsive element, and the core Rta-responsive element was mapped to a 26-bp region spanning from nucleotide 18315 to 18290 on the viral genome. We propose that the existence of two vIL-6 promoters offers opportunities for differential regulation of vIL-6 gene expression in different tissue types and may account for the variable vIL-6 levels observed in KS, PEL, and MCD.
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PMID:Transcriptional regulation of the interleukin-6 gene of human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus). 1213 31

Human herpesvirus 8 (HHV-8)/Kaposi sarcoma-associated herpesvirus (KSHV) is linked to a number of malignancies thought to be driven by cytokines, including interleukin-6 (IL-6). Rta, a transcriptional activator encoded by HHV-8/KSHV, activates the viral lytic cycle leading to the expression of several viral genes implicated in viral pathogenesis. However, the effect of HHV-8/KSHV Rta on cellular genes has not been reported. We present evidence that the human IL-6 (hIL-6) gene is up-regulated by Rta. Rta potently activated (up to 164-fold) the hIL-6 promoter in a dose-dependent manner in a transient transfection reporter system. Rta also induced expression of the endogenous hIL-6 gene, as shown by enzyme-linked immunosorbent assays. Activation of the hIL-6 gene by HHV-8/KSHV supports the role of hIL-6 in the development of these malignancies.
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PMID:Rta of the human herpesvirus 8/Kaposi sarcoma-associated herpesvirus up-regulates human interleukin-6 gene expression. 1217 19

The ILRE (interleukin response element) contained within the promoter of the interleukin-6 (IL-6) gene is defined as the site recognized by the p65 NF-kappaB transcriptional activator and is crucial for activation of the IL-6 gene. The region of the promoter containing the ILRE is complex containing a CCAAT enhancer-binding protein (C/EBP) site immediately upstream of the ILRE, which is required for optimal activation of the IL-6 gene. Additionally, the ILRE overlaps a site that is recognized by the mammalian transcriptional repressor RBP (CBF-1), and RBP binding within the ILRE region represses activated IL-6 expression. In this study, the complexity of this region is further revealed by the identification of a second nested C/EBP site, which overlaps that of RBP and therefore also the ILRE. Optimal activation requires both the upstream and newly identified C/EBP sites in conjunction with the p65 NF-kappaB binding site. We previously reported that RBP represses IL-6 activation but does not target p65. We extend these analyses here to show that RBP binding does not occlude p65 from binding but instead directly overlaps the newly identified downstream C/EBP site, thereby impeding p65-C/EBP-mediated co-activation. This result suggests a role for RBP in the repression of other genes containing a C/EBP site that exhibits sequence overlap with the RBP site.
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PMID:Binding of C/EBP and RBP (CBF1) to overlapping sites regulates interleukin-6 gene expression. 1220 Apr 47

Brain injuries trigger physiological reactions which are mediated by a number of cytokines including interleukin-6 (IL-6), ciliary neurotrophic factor (CNTF), and leukemia inhibitory factor (LIF). Astrocytes and microglia, the protagonists in these traumatic responses, are known to secrete a variety of paracrine signals. Oligodendrocytes are involved as well and constitute another possible source of cytokines. Here we show the expression of IL-6, CNTF, and LIF in OLN-93 cells, derived from rat oligodendrocyte primary cultures. While differential gene transcription after injury has been described for many cytokines, the regulation of these physiological responses is unknown in many instances. Recent experiments indicate that the transcriptional activator retinoic acid (RA) plays a role in peripheral nerve regeneration. Transcripts of the retinoic acid receptors and the retinoid X receptors were also detected in OLN-93 oligodendrocytes. Using quantitative RT-PCR, we have therefore investigated the effect of RA on the expression of neuropoietic cytokines in these cells. Treatment with 1 microM all- trans RA for 24 h increased the mRNA concentration of LIF by a factor of 3.1 ( P<0.01). In contrast, RA had no significant effect on the expression of CNTF. The results suggest RA as a possible regulator of cytokine signaling in the CNS.
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PMID:Retinoic acid enhances leukemia inhibitory factor expression in OLN-93 oligodendrocytes. 1239 70

To understand the interaction between the virus and its host, we used three sources of cDNA microarrays to examine the expression of 12,309 unique genes at 6 h postinfection of HeLa cells with high multiplicities of adenovirus type 2. Seventy-six genes with significantly changed expression ratios were identified, suggesting that adenovirus only modulates expression of a limited set of cellular genes. Quantitative real-time PCR analyses on selected genes were performed to confirm the microarray results. Significantly, a pronounced transcriptional activation by the promiscuous E1A-289R transcriptional activator was not apparent. Instead, promoter sequences in 45% of the upregulated genes harbored a potential E2F binding site, suggesting that the ability of the amino-terminal domain of E1A to regulate E2F-dependent transcription may be a major pathway for regulation of cellular gene expression. CDC25A was the only upregulated gene directly involved in cell cycle control. In contrast, several genes implicated in cell growth arrest were repressed. The transforming growth factor beta superfamily was specifically affected in the expression of both the upstream ligand and an intracellular regulator. In agreement with previous reports, adenovirus also targeted the innate immune response by downregulating several cytokines, including CLL2, CXCL1, and interleukin-6. Finally, stress response genes encoding GADD45B, ATF3, and TP53AP1 were upregulated. Importantly, we also found a novel countermeasure-activation of the apoptosis inhibitor survivin.
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PMID:Strategic attack on host cell gene expression during adenovirus infection. 1451 49


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