Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.6 (RNA polymerase)
34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

IL-8 is a chemokine that recruits migrating neutrophils and leukocytes to areas of inflammation. In noninflamed tissue, IL-8 expression is low but can be rapidly induced by proinflammatory cytokines. Typically, inflammation and transient IL-8 expression are beneficial. However, some diseases are characterized by excessive inflammation and high levels of IL-8. Previous studies have shown that IFN-beta can inhibit the expression of IL-8, although the mechanism is unknown. Using chromatin immunoprecipitation assays, we define the IL-8 transcriptional program in the absence or presence of inducing stimuli and/or inhibition by IFN-beta. In the absence of stimuli, the IL-8 promoter is acetylated but negatively regulated by corepressor proteins. Upon PMA stimulation, the levels of these corepressors are reduced and the promoter is rapidly bound and activated by transcription factors, including NF-kappaB p65, C/EBPbeta, and c-Fos. In addition, RNA polymerase II is recruited to the IL-8 promoter to initiate transcription. However, in the presence of both PMA and IFN-beta, there are diminished levels of histone acetylation, reduced levels of transcription factors such as NF-kappaB p65 and RNA polymerase II, and an increased presence of corepressor proteins such as histone deacetylases 1 and 3 and silencing mediator of retinoic acid and thyroid hormone receptors. IFN-gamma-inducible protein-10 and MCP-1 genes, also regulated by NF-kappaB, are unaffected by IFN-beta, and IFN-beta does not prevent the activation, nuclear migration, or binding of NF-kappaB p65 to the kappaB element of the IFN-gamma-inducible protein-10 promoter. As such, these data show that the inhibitory effects of IFN-beta are specific to the IL-8 promoter.
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PMID:Mechanism of IFN-beta-mediated inhibition of IL-8 gene expression in astroglioma cells. 1681 36

Infection of endothelial cells by Listeria monocytogenes is an essential step in the pathogenesis of listeriosis. Small GTPases of the Rho family act as molecular switches in signal transduction. We tested the hypothesis that Rho GTPases contribute to the regulation of cytokine expression following L. monocytogenes infection. L. monocytogenes induced release of distinct CC and CXC, as well as Th1 and Th2 cytokines and growth factors by endothelial cells and activated RhoA and Rac1. Inhibition of Rac1 by inhibitor Nsc23766 reduced cytokine expression, and slightly yet significantly the uptake of bacteria. Blocking of Rho proteins by Clostridium difficile toxin B-10463 (TcdB) reduced Listeria-dependent cytokine expression, whereas activating Rho proteins by Escherichia coli CNF1 increased it. We analyzed regulation of IL-8 expression in more detail: Listeria-induced IL-8 release was reduced by inhibition of RhoA, Rac1 and Cdc42 (TcdB) or Rac1 while blocking of RhoA/B/C by Clostridium limosum C3 fusion toxin (C3FT) or Rho kinase by Y27632 reduced cytokine expression only slightly. Activation of RhoA, Rac1 and Cdc42 (CNF1), but not of RhoA alone (CNF(Y)), enhanced Listeria-dependent IL-8 release significantly. Furthermore, inhibition of RhoA, Rac1 and Cdc42 (TcdB) and Rac1 (Nsc23766), but not of RhoA (C3FT) reduced Listeria-related recruitment of NF-kappaB/p65 and RNA polymerase II to the il8 promoter, as well as acetylation of histone H4 and Ser10/Lys14-phosphorylation/acetylation of histone H3 at the il8 gene promoter in HUVEC. In conclusion, Rac1 contributed to L. monocytogenes-induced cytokine expression by human endothelial cells.
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PMID:Listeria monocytogenes induced Rac1-dependent signal transduction in endothelial cells. 1688 94

We have previously demonstrated that the transcription factor NF-kappaB is activated by histone deacetylase inhibitors in a PI3K/Akt-dependent manner. The molecular mechanisms governing this process have not been well described. By virtue of their inhibitory action, it is unclear whether the addition of histone deacetylase inhibitors simply preserves the acetylation status of RelA/p65 or whether they actively stimulate signaling cascades that result in increased acetylation and transcription of NF-kappaB. Here we provide evidence that suberoylanilide hydroxamic acid stimulates NF-kappaB transcription through a signaling cascade that involves activation of both the serine/threonine kinase Akt and the p300 acetyltransferase. Using newly developed phosphospecific antibodies to p300 (pSer(1834)), and site-directed mutant proteins, we find that suberoylanilide hydroxamic acid stimulates Akt activity, which is required to phosphorylate p300 at Ser(1834). Akt-mediated phosphorylation of p300 dramatically increases its acetyltransferase activity as measured by an increased acetylation of RelA/p65 at Lys(310), a modification that is required for full NF-kappaB transcription. Importantly, coordinate activation of Akt/p300 pathway by suberoylanilide hydroxamic acid occurs at the chromatin level, resulting in recruitment of activated Akt (pSer(473)), p300 (pSer(1834)), acetylated RelA/p65 (Lys(310)), and RNA polymerase II to the NF-kappaB-dependent cIAP-2 and Bfl-1/A1 promoters. These studies provide evidence that histone deacetylase inhibitors, such as suberoylanilide hydroxamic acid, not only inhibit deacetylase activity but also stimulate active NF-kappaB transcription and cell survival through signaling pathways involving Akt and increased p300 acetyltransferase activity.
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PMID:Suberoylanilide hydroxamic acid induces Akt-mediated phosphorylation of p300, which promotes acetylation and transcriptional activation of RelA/p65. 1692 51

Legionella pneumophila causes community-acquired pneumonia with high mortality, but little is known about its interaction with the alveolar epithelium. The aim of this study was to investigate whether L. pneumophila infection of lung epithelial cells (A549) resulted in pro-inflammatory activation. L. pneumophila infection induced liberation of interleukin (IL)-2, -4, -6, -8 and -17, monocyte chemoattractant protein-1, tumour necrosis factor-alpha, IL-1beta, interferon-gamma and granulocyte colony-stimulating factor, but not of IL-5, -7, -10, -12 (p70) or -13 or granulocyte-macrophage colony-stimulating factor. The present study focused on IL-8 and found induction by L. pneumophila strains 130b, Philadelphia 1, Corby and, to a lesser extent, JR32. Knockout of dotA, a central gene involved in type IVB secretion, did not alter IL-8 induction, whereas lack of flagellin significantly reduced IL-8 release by Legionella. Moreover, p38 mitogen-activated protein kinase (MAPK) was activated and kinase inhibition reduced secretion of induced cytokines, with the exception of IL-2 and granulocyte colony-stimulating factor. In contrast, inhibition of the MAPK kinase 1/extracellular signal-regulated kinase pathway only reduced the expression of a few cytokines. L. pneumophila also induced binding of nuclear factor-kappaB subunit RelA/p65 and RNA polymerase II to the il8 promoter, and a specific inhibitor of the inhibitor of nuclear factor-kappaB complex dose-dependently lowered IL-8 expression. Taken together, Legionella pneumophila activated p38 mitogen-activated protein kinase- and nuclear factor-kappaB/RelA pathway-dependent expression of a complex pattern of cytokines by human alveolar epithelial cells, presumably contributing to the immune response in legionellosis.
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PMID:Legionella pneumophila-induced NF-kappaB- and MAPK-dependent cytokine release by lung epithelial cells. 1697 6

In the temporomandibular joint (TMJ) synovium, cyclo-oxygenase-2 (COX-2) expression has been believed to be directly related to joint pain and synovitis. Here we investigated the role of Nuclear Factor kappaB (NF-kappaB) in the regulation of COX-2 expression in synovial fibroblasts from human TMJ induced by tumor necrosis factor-alpha (TNF-alpha). By reverse-transcriptase/polymerase chain-reaction (RT-PCR) and Western blotting analysis, TNF-alpha induced a dose- and time-dependent increase in COX-2 expression. Electrophoretic mobility shift assay (EMSA) revealed that transient NF-kappaB activation in the COX-2 promoter was triggered by TNF-alpha. In parallel with transient NF-kappaB activation, the rapid translocation of NF-kappaB, particularly the p65 subunit, from the cytoplasm into the nucleus was demonstrated. Pre-treatment with pyrolidine dithiocarbamate (PDTC), one of the NF-kappaB inhibitors, prevented binding to the COX-2 promoter and expression of COX-2 protein in response to TNF-alpha. These findings indicate that activation of NF-kappaB is responsible for TNF-alpha-induced COX-2 expression in synovial fibroblasts from the TMJ.
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PMID:Role of NF-kappaB in TNF-alpha-induced COX-2 expression in synovial fibroblasts from human TMJ. 1738 33

Atherosclerosis develops in distinct regions of the arterial tree. Defining patterns and mechanisms of endothelial cell gene expression in different regions of normal arteries is key to understanding the initial molecular events in atherogenesis. In this study, we demonstrated that the expression of endothelial nitric-oxide synthase (eNOS), an atheroprotective gene, and its phosphorylation on Ser(1177), a marker of activity, were lower in regions of the normal mouse aorta that are predisposed to atherosclerosis. The same expression pattern was observed in mouse strains that are both susceptible and resistant to atherosclerosis, and the topography of eNOS expression was inverse to p65, the main nuclear factor-kappaB subunit. Modeling of disturbed and uniform laminar flow in vitro reproduced the expression patterns of eNOS and p65 that were found in vivo. Heterogeneous nuclear RNA expression and RNA polymerase II chromosome immunoprecipitation studies demonstrated that regulation of transcription contributed to increased eNOS expression in response to shear stress. In vivo, the transcription of eNOS was reduced in regions of the mouse aorta predisposed to atherosclerosis, as defined by reporter gene expression in eNOS promoter-beta-galactosidase reporter transgenic mice. These data suggest that disturbed hemodynamic patterns found at arterial branches and curvatures uniquely modulate endothelial cell gene expression by regulating transcription, potentially explaining why these regions preferentially develop atherosclerosis when risk factors such as hypercholesterolemia are introduced.
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PMID:Relative reduction of endothelial nitric-oxide synthase expression and transcription in atherosclerosis-prone regions of the mouse aorta and in an in vitro model of disturbed flow. 1798 33

Abnormal nuclear factor-kappaB (NF-kappaB) signaling has been attributed to the initiation and progression of cancer. Posttranslational modification of p65 facilitates optimal NF-kappaB signaling after activation. Here, we show that the phosphorylation of serine 536 was required for p65-mediated transcription and I kappa B alpha expression in fibroblasts. Furthermore, tumor necrosis factor (TNF) treatment slightly induced p65 phosphorylation, and both unphosphorylated and phosphorylated p65 translocated into the nucleus. The phosphorylation of serine 536 was not required for p65-mediated protection from TNF cytotoxicity and Traf1 induction in fibroblasts. Also, the corecruitment of p65 and RNA polymerase II to the Traf1 enhancer region did not require p65 phosphorylation. However, the corecruitment of p65 and RNA polymerase II to the Csf2 promoter required the phosphorylation of serine 536. These findings suggested that the requirement of serine phosphorylation at residue 536 and the distance between the NF-kappaB response element and the start of transcription may influence which genes will be transcribed.
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PMID:Traf1 induction and protection from tumor necrosis factor by nuclear factor-kappaB p65 is independent of serine 536 phosphorylation. 1805 47

Inflammatory activation of the endothelium by Chlamydophila pneumoniae infection has been implicated in the development of chronic vascular lesions and coronary heart disease by seroepidemiological and animal studies. We tested the hypothesis that C. pneumoniae induced inflammatory gene expression is regulated by Rho-GTPase-related histone modifications. C. pneumoniae infection induced the liberation of proinflammatory interleukin-6, interleukin-8, granulocyte colony-stimulating factor, macrophage inflammatory protein-1beta, granulocyte/macrophage colony-stimulating factor, and interferon-gamma by human endothelial cells. Cytokine secretion was reduced by simvastatin and the specific Rac1 inhibitor NSC23766 but was synergistically enhanced by inhibitors of histone deacetylases trichostatin A and suberoylanilide hydroxamic acid. Infection of endothelial cells with viable C. pneumoniae, but not exposure to heat-inactivated C. pneumoniae or infection with C. trachomatis, induced acetylation of histone H4 and phosphorylation and acetylation of histone H3. Pretreatment of C. pneumoniae-infected cells with simvastatin or NSC23766 reduced global histone modifications as well as specific modifications at the il8 gene promoter, as shown by chromatin immunoprecipitation. Reduced recruitment of nuclear factor kappaB p65/RelA as well as of RNA polymerase II was observed in statin-treated cells. Taken together, Rac1-mediated histone modifications seem to play an important role in C. pneumoniae-induced cytokine production by human endothelial cells.
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PMID:Simvastatin reduces Chlamydophila pneumoniae-mediated histone modifications and gene expression in cultured human endothelial cells. 1843 97

Interleukin-1 (IL-1)-induced mRNA expression of ccl2 (also called MCP-1), a prototypic highly regulated inflammatory gene, is severely suppressed in cells lacking c-Jun or Jun N-terminal protein kinase 1 (JNK1)/JNK2 genes and is only partially restored in cells expressing a c-Jun(SS63/73AA) mutant protein. We used chromatin immunoprecipitation to identify three c-Jun-binding sites located in the far 5' region close to the transcriptional start site and in the far 3' region of murine and human ccl2 genes. Mutational analysis revealed that the latter two sites contribute to ccl2 transcription in response to the presence of IL-1 or of ectopically expressed c-Jun-ATF-2 dimers. Further experiments comparing wild-type and c-Jun-deficient cells revealed that c-Jun regulates Ser10 phosphorylation of histone H3, acetylation of histones H3 and H4, and recruitment of histone deacetylase 3 (HDAC3), NF-kappaB subunits, and RNA polymerase II across the ccl2 locus. c-Jun also coimmunoprecipitated with p65 NF-kappaB and HDAC3. Based on DNA microarray analysis, c-Jun was required for full expression of 133 out of 162 IL-1-induced genes. For inflammatory genes, these data support the idea of an activator function of c-Jun that is executed by multiple mechanisms, including phosphorylation-dependent interaction with p65 NF-kappaB and HDAC3 at the level of chromatin.
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PMID:c-Jun controls histone modifications, NF-kappaB recruitment, and RNA polymerase II function to activate the ccl2 gene. 1844 42

The Epstein-Barr virus (EBV)-encoded latent membrane protein-1 (LMP1), a functional homologue of the tumor necrosis factor receptor family, substantially contributes to EBV's oncogenic potential by activating nuclear factor-kappaB (NF-kappaB). miR-155 is an oncogenic miRNA critical for B-cell maturation and immunoglobulin production in response to antigen. We report that miR-155 expression is much higher in EBV-immortalized B cells than in EBV-negative B cells. LMP1, but not LMP2, up-regulated the expression of miR-155, when transfected in EBV-negative B cells. We analyzed two putative NF-kappaB binding sites in the miR-155 promoter; both sites recruited NF-kappaB complex, in nuclear extract from EBV-immortalized cells. The exogenous expression of LMP1, in EBV-negative background, is temporally correlated to induction of p65 with binding on both NF-kappaB sites and with miR-155 overexpression. The induction of p65 binding together with increased RNA polymerase II binding, confirms that LMP1-mediated activation of miR-155 occurs transcriptionally. In reporter assays, miR-155 promoter lacking NF-kappaB binding sites was no longer activated by LMP1 expression and an intact AP1 site is needed to attain maximum activation. Finally, we demonstrate that LMP1-mediated activation of miR-155 in an EBV-negative background correlates with reduction of protein PU.1, which is a possible miR target.
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PMID:Epstein-Barr virus latent membrane protein 1 trans-activates miR-155 transcription through the NF-kappaB pathway. 1894 Aug 71


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