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)

Hepatocyte nuclear factor 4 (HNF-4) is a key member of the transcription factor network regulating hepatocyte differentiation and function. Activation of the HNF-4 gene involves physical interaction between a distant enhancer and the proximal promoter region, bound by distinct sets of transcription factors. Here we report that, upon mitogen-activated protein (MAP) kinase activation, HNF-4 expression is downregulated in human hepatoma cells. This effect is mediated by the loss of CEBPalpha expression. During MAP kinase signaling, the recruitment of HNF-3beta and HNF-1alpha to the HNF-4 enhancer and RNA polymerase II to the proximal HNF-4 promoter was compromised. CBP, Brg1, and TFIIB were also dissociated from the HNF-4 regulatory regions, and the enhancer-promoter complex was disrupted. Interestingly, the extent of nucleosome acetylation did not decrease at either regulatory region, and HNF-6 and HNF-1alpha, as well as components of the TFIID, remained associated with the proximal promoter during the repressed state. The results point to an absolute requirement of enhancer-promoter communication for maintaining the active state of the HNF-4 gene and provide evidence for a molecular bookmarking mechanism, which may contribute to the prevention of permanent silencing of the locus during the repressed state.
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PMID:Mitogen-activated protein kinase-mediated disruption of enhancer-promoter communication inhibits hepatocyte nuclear factor 4alpha expression. 1698 Jun 7

The physiological and pathological manifestations of Sonic hedgehog (Shh) signaling arise from the specification of unique transcriptional programs dependent upon key nuclear effectors of the Ci/Gli family of transcription factors. However, the underlying mechanism by which Gli proteins regulate target gene transcription in the nucleus remains poorly understood. Here, we identify and characterize a physical and functional interaction between Gli3 and the MED12 subunit within the RNA polymerase II transcriptional Mediator. We show that Gli3 binds to MED12 and intact Mediator both in vitro and in vivo through a Gli3 transactivation domain (MBD; MED12/Mediator-binding domain) whose activity derives from concerted functional interactions with both Mediator and the histone acetyltransferase CBP. Analysis of MBD truncation mutants revealed an excellent correlation between the in vivo activation strength of an MBD derivative and its ability to bind MED12 and intact Mediator in vitro, indicative of a critical functional interaction between the Gli3 MBD and the MED12 interface in Mediator. Disruption of the Gli3-MED12 interaction through dominant-negative interference inhibited, while RNA interference-mediated MED12 depletion enhanced, both MBD transactivation function and Gli3 target gene induction in response to Shh signaling. We propose that activated Gli3 physically targets the MED12 interface within Mediator in order to functionally reverse Mediator-dependent suppression of Shh target gene transcription. These findings thus link MED12 to the modulation of Gli3-dependent Shh signaling and further implicate Mediator in a broad range of developmental and pathological processes driven by Shh signal transduction.
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PMID:Mediator modulates Gli3-dependent Sonic hedgehog signaling. 1700 Jul 79

More than fifteen years following the description of Tat as a critical HIV gene expression regulatory protein, additional roles for Tat in HIV replication have been described, including reverse transcription. Tat achieves function through direct interaction with viral proteins, including reverse transcriptase, and numerous cellular proteins including cyclin T1, RNA polymerase II, protein kinase R (PKR), p300/CBP, and P/CAF. Despite our advanced knowledge of how Tat operates, this has not yet resulted in the discovery of effective agents capable of targeting various Tat functions. Nevertheless, Tat remains an attractive, virus-specific molecule and detailed understanding of specific protein interaction holds promise for future drug discovery.
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PMID:Will diverse Tat interactions lead to novel antiretroviral drug targets? 1716 34

Tumor necrosis factor-alpha (TNF-alpha) is a potent mediator of inflammation, inducing expression of a gene network mediated by NF-kappaB. Previously we found that TNF-alpha-induced reactive oxygen species (ROS) production is required for NF-kappaB action because antioxidants inhibited TNF-alpha-inducible IL-8 expression without affecting its nuclear translocation. Here, we further investigated this ROS pathway controlling NF-kappaB/RelA dependent gene expression. We observed that TNF-alpha enhanced ROS production approximately 2-fold 20 min after stimulation and significantly increased oxidative DNA damage (8-oxoguanine lesions) over controls. Treatment with chemically unrelated antioxidants specifically inhibited expression of TNF-inducible NF-kappaB-dependent genes without producing detectable cytotoxicity or affecting GAPDH expression. We found that TNF-alpha-induced NF-kappaB/RelA Ser(276) phosphorylation, a modification critical for its transcriptional activity, was inhibited by abrogation of the ROS signaling pathway, whereas NF-kappaB/RelA Ser(536) phosphorylation was not. Interestingly, antioxidant treatment selectively inhibited TNF-alpha-induced catalytic activity of cAMP dependent protein kinase A (PKAc) but not mitogen-stress related kinase-1 (MSK1), kinases known to phosphorylate RelA at Ser(276). Using PKAc inhibitors and siRNA mediated PKAc knockdown, TNF-alpha-induced Ser(276) phosphorylation and IL-8 expression were both significantly reduced, indicating PKAc is required for RelA Ser(276) phosphorylation. Consistently, a site mutation of Rel A (Ser(276) to Ala) in RelA-deficient embryonic fibroblasts failed to activate IL-8 Luciferase activity in response to TNF-alpha. Furthermore, TNF-alpha-inducible NF-kappaB/RelA interaction with the co-activator CBP/p300, essential for enhanceosome formation, was attenuated by antioxidant treatment. Using chromatin immunoprecipitation assay (ChIP), we observed that recruitment of p300 and RNA polymerase II (Pol II) to the IL-8 promoter was also abrogated by antioxidant. These results indicate that the ROS-mediated TNF-alpha-induced IL-8 transcription is regulated by NF-kappaB/RelA phosphorylation at the critical Ser(276) residue by PKAc, resulting in stable enhanceosome formation on target genes. These studies provide insight into a novel antioxidant-sensitive pathway that can be targeted to inhibit NF-kappaB-mediated inflammation.
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PMID:TNF-alpha-induced NF-kappaB/RelA Ser(276) phosphorylation and enhanceosome formation is mediated by an ROS-dependent PKAc pathway. 1731 4

Cajal bodies (CBs) in oocytes of the house cricket Acheta domesticus are large, perfectly spherical nuclear organelles with a complex internal structure. These consist of a fibrillar coilin-containing matrix and a central cavity with a prominent fibrogranular body inside; the latter has been referred to as an "internal" interchromatin granule cluster (IGC). Within the matrix of CBs we detected transcriptional co-activators CBP/p300 and TATA-box binding protein (TBP). No RNA polymerase II was revealed in CBs of both normal and actynomycin D treated oocytes. In the nucleoplasm of A. domesticus oocytes, besides CBs, free IGCs were observed. In oocytes treated with actynomycin D, the amount of "free" IGCs in the nucleoplasm increase significantly, granular and fibrillar components of IGCs were seen segregated, and RNA polymerase II and CBP/p300 were found to be accumulated in fibrillar zones of IGCs.
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PMID:[Cajal bodies in insect oocytes. II. New data on the molecular composition of cajal bodies in oocytes of the house cricket Acheta domesticus with special reference to interactions between cajal bodies and interchromatin granule clusters]. 1743 2

The female gonad (germovitellarium) of the lecithoepitheliate turbellarians has a special type of organization. It consists of the peculiar follicles in which the oocytes develop surrounded by the yolk cells (vitellocytes). While an oocyte grows, chromatin remains to be decondensed, and the karyosphere is not formed. Using immunogold labeling microscopy we studied a distribution of RNA polymerase II, transcriptional coactivators CBP/p300, and TATA-box binding protein in the perichromatin regions of Geocentrophora baltica oocytes. We found these components of RNA polymerase II transcription to be associated with the perichromatin fibrils (PFs). We suggest that the presence of numerous PFs in the perichromatin regions of G. baltica oocytes reflects the active state of the nucleus during the unusual alimentary oogenesis of Lecithoepitheliata.
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PMID:[Oogenesis in turbellarians of the genus Geocentrophora (Lecithoepitheliata, Prorhynchidae) studied by light and electron microscopy. VI. Immunogold labeling localization of some components essential for RNA polymerase II transcription in perichromatin regions of G. baltica oocytes]. 1758 97

Downregulation of the transporter associated with antigen processing 1 (TAP-1) has been observed in many tumors and is closely associated with tumor immunoevasion mechanisms, growth, and metastatic ability. The molecular mechanisms underlying the relatively low level of transcription of the tap-1 gene in cancer cells are largely unexplained. In this study, we tested the hypothesis that epigenetic regulation plays a fundamental role in controlling tumor antigen processing and immune escape mechanisms. We found that the lack of TAP-1 transcription in TAP-deficient cells correlated with low levels of recruitment of the histone acetyltransferase, CBP, to the TAP-1 promoter. This results in lower levels of histone H3 acetylation at the TAP-1 promoter, leading to a decrease in accessibility of the RNA polymerase II complex to the TAP-1 promoter. These observations suggest that CBP-mediated histone H3 acetylation normally relaxes the chromatin structure around the TAP-1 promoter region, allowing transcription. In addition, we found a hitherto-unknown mechanism wherein interferon gamma up-regulates TAP-1 expression by increasing histone H3 acetylation at the TAP-1 promoter locus. These findings lie at the heart of understanding immune escape mechanisms in tumors and suggest that the reversal of epigenetic codes may provide novel immunotherapeutic paradigms for intervention in cancer.
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PMID:Epigenetic control of the immune escape mechanisms in malignant carcinomas. 1787 43

Ontogeny requires the coordinated regulation of multigene programs by a plethora of extracellular and intracellular signals, thereby allowing cells to transition between different states, including proliferation and differentiation. Disruption of this regulation can result in oncogenic transformation in which cells are "arrested" in the proliferative state. This article summarizes our current understanding of a novel "Integrative Nuclear Fibroblast Growth Factor Receptor-1 (FGFR1) Signaling" (INFS) pathway, which influences differentiation of neural progenitor cells and the associated gene activities. Activation of cell surface neurotransmitter, hormonal, or growth factor receptors stimulates the release of FGFR1 from cytoplasmic membranes into the cytosol. This process is enabled by the atypical transmembrane domain of FGFR1 and is facilitated by the interaction with pp90 ribosomal S6 kinase-1. Cytosolic FGFR1 is transported into the nucleus by importin beta and activates transcription in cooperation with CBP (cyclic AMP Responsive Element-Binding Protein) by augmenting RNA polymerase II activity and histone acetylation. To explain the developmental function of FGFR1, a "feed-forward-and-gate" signaling mechanism is presented in which the INFS pathway "feeds forward" the developmental signals to the common and essential transcriptional coactivator, CBP. The coupled activation of CBP (by INFS) and transcription factors (by specific signaling pathways) enables the coordinated regulation of multigene programs by developmental cues. In some cancer cells, in which INFS is inactive, the reconstitution of nuclear FGFR1 signaling may be used to reestablish this coordinated regulation thereby inhibiting tumor cell proliferation and inducing differentiation.
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PMID:Integrative nuclear signaling in cell development--a role for FGF receptor-1. 1802 Oct 9

Signal transduction pathways often use a transcriptional component to mediate adaptive cellular responses. Coactivator proteins function prominently in these pathways as the conduit to the basic transcriptional machinery. Here we present a high-throughput cell-based screening strategy, termed the "coactivator trap," to study the functional interactions of coactivators with transcription factors. We applied this strategy to the cAMP signaling pathway, which utilizes two families of coactivators, the cAMP response element binding protein (CREB) binding protein (CBP)/p300 family and the recently identified transducers of regulated CREB activity family (TORCs1-3). In addition to identifying numerous known interactions of these coactivators, this analysis identified NONO (p54(nrb)) as a TORC-interacting protein. RNA interference experiments demonstrate that NONO is necessary for cAMP-dependent activation of CREB target genes in vivo. Furthermore, TORC2 and NONO complex on cAMP-responsive promoters, and NONO acts as a bridge between the CREB/TORC complex and RNA polymerase II. These data demonstrate the utility of the coactivator trap by identification of a component of cAMP-mediated transcription.
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PMID:A coactivator trap identifies NONO (p54nrb) as a component of the cAMP-signaling pathway. 1807 67

Curcumin, a phenolic compound from the curry spice turmeric, exhibits a wide range of activities in eukaryotic cells, including antiviral effects that are at present incompletely characterized. Curcumin is known to inhibit the histone acetyltransferase activity of the transcriptional coactivator proteins p300 and CBP, which are recruited to the immediate early (IE) gene promoters of herpes simplex virus type 1 (HSV-1) by the viral transactivator protein VP16. We tested the hypothesis that curcumin, by inhibiting these coactivators, would block viral infection and gene expression. In cell culture assays, curcumin significantly decreased HSV-1 infectivity and IE gene expression. Entry of viral DNA to the host cell nucleus and binding of VP16 to IE gene promoters was not affected by curcumin, but recruitment of RNA polymerase II to those promoters was significantly diminished. However, these effects were observed using lower curcumin concentrations than those required to substantially inhibit global H3 acetylation. No changes were observed in histone H3 occupancy or acetylation at viral IE gene promoters. Furthermore, p300 and CBP recruitment to IE gene promoters was not affected by the presence of curcumin. Finally, disruption of p300 expression using a short hairpin RNA did not affect viral IE gene expression. These results suggest that curcumin affects VP16-mediated recruitment of RNA polymerase II to IE gene promoters by a mechanism independent of p300/CBP histone acetyltransferase activity.
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PMID:Curcumin inhibits herpes simplex virus immediate-early gene expression by a mechanism independent of p300/CBP histone acetyltransferase activity. 1819 76


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