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)

Binding sites for the dimeric transcription factor activator protein (AP)-1 are found in numerous immunoregulatory and inflammatory genes. The precise mechanisms by which AP-1 activates or represses immune response genes and in particular the roles of individual AP-1 subunits in inflammatory responses are largely unknown. We report here that c-Fos and Fos-related antigen-1 (Fra-1), two inducible components of AP-1, are recruited to the endogenous interleukin (IL)-8 promoter in an IL-1-dependent manner. c-Fos activates IL-8 transcription and synergizes in this effect with p65 NF-kappaB. In contrast, Fra-1 strongly inhibits inducible IL-8 transcription. Fra-1 activation involves its stabilization, ubiquitination, and interaction with histone deacetylase-1. Blockade of MEK1 by PD98059 suppresses c-Fos and Fra-1 expression and, thus, affects two counteractive signals for IL-8 mRNA synthesis simultaneously. This disturbs the inducible recruitment of TATA box-binding protein and RNA polymerase II to the IL-8 promoter. Additional experiments reveal that, in conjunction with p65 NF-kappaB, the MEK1-ERK-dependent synthesis of c-Fos and Fra-1 serves to adjust the overall expression level of IL-8 in response to two of its physiological inducers, IL-1 and epidermal growth factor. Relative to c-Fos, the delayed recruitment of Fra-1 to the IL-8 promoter provides an example how AP-1 subunits may dampen excessive chemokine synthesis.
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PMID:MEK1-dependent delayed expression of Fos-related antigen-1 counteracts c-Fos and p65 NF-kappaB-mediated interleukin-8 transcription in response to cytokines or growth factors. 1561 16

Vascular endothelial growth factor (VEGF) is a dimeric heparin-binding glycoprotein that is a potent endothelial cell-specific mitogen with increased expression during adult cutaneous wound healing. VEGF activity is mediated by two receptors, VEGFR-1 (Flt-1) and VEGFR-2 (Flk-1/KDR), which are expressed primarily in vascular endothelial cells. Initiation of profibrotic cytokine expression likely coordinates the transition from scarless healing to scar formation in fetal wounds. Angiogenesis is an important component of the scarring repair process, but the function of VEGF and degree of angiogenesis during scarless repair has not been investigated. We hypothesize that VEGF and its receptors are differentially expressed in scarless compared with scarring fetal wounds because VEGF is implicated in angiogenesis during skin development and adult wound healing. Excisional wounds were created on fetal rats at gestational ages 16.5 days (E16) and 18.5 days (E18) (term = 21.5 days). Wounds were harvested at 24 and 72 hours (n = 12 wounds per time point). Nonwounded fetal skin (E17, E19, and E21) was used as control. Reduced-cycle, specific-primer, reverse-transcriptase polymerase chain reaction was performed to determine the expression of VEGF and its receptors, VEGFR-1 and VEGFR-2. Wounds at 72 hours and fetal skin controls were examined under high-power microscopy for blood vessel counts. Unpaired two-tailed t test was used (p < 0.05 was considered significant). VEGF expression increased 2.4-fold (p < 0.001) during normal skin development from E17 to E19. In scarless wounds (E16), VEGF expression increased 2.8-fold (p < 0.02) at 72 hours. No increased expression occurred in the scarring wounds (E18). VEGFR-1 and VEGFR-2 expression increased over 2-fold during normal skin development from E17 to E21. However, each was down-regulated 30 to 50 percent in scarless (E16) and scarring (E18) wounds. There is a 2-fold increase in mean vessel counts per high-power field in scarless (E16) wounds at 72 hours compared with age-matched control skin (p < 0.02) and a 1.7-fold increase in mean vessel count in scarring fetal wounds (E18) compared with age-matched control skin (p < 0.05). There is no difference in the total number of vessels found in scarless versus scarring wounds or between 19.5-day versus 21.5-day fetal skin. VEGF and its receptors, VEGFR-1 and VEGFR-2, increase expression during skin development and dermal differentiation. VEGF expression quickly elevates during scarless compared with scarring repair, which likely contributes to the more rapid scarless fetal repair rate. Similar numbers of new ves-sels are formed during scarless and scarring fetal repair.
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PMID:Increased angiogenesis and expression of vascular endothelial growth factor during scarless repair. 1562 52

Influenza virus RNA-dependent RNA polymerase is a heterotrimeric complex of PB1, PB2, and PA. We show that the individually expressed PB2 subunit can be assembled with the coexpressed PB1-PA dimer in vitro into a transcriptionally active complex. Furthermore, we demonstrate that a model viral RNA promoter can bind to the PB1-PA dimer prior to assembly with PB2. Our results are consistent with a recently proposed model for the sequential assembly of viral RNA polymerase complex in which the PB1-PA dimeric complex and the PB2 monomer are transported into the nucleus separately and then assembled in the nucleus.
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PMID:In vitro assembly of PB2 with a PB1-PA dimer supports a new model of assembly of influenza A virus polymerase subunits into a functional trimeric complex. 1595 11

The orphan nuclear hormone receptor estrogen-related receptor alpha (ERRalpha, NR3B1) is a constitutive transcription factor that is structurally and functionally related to the classic estrogen receptors. ERRalpha can recognize both the estrogen response element and its own binding site (ERRE) in either dimeric or monomeric forms. ERRalpha is also a phosphoprotein whose expression in human breast tumors correlates with that of the receptor tyrosine kinase ErbB2, suggesting that its transcriptional activity could be regulated by signaling cascades. Here, we investigated growth factor regulation of ERRalpha function and found that it is phosphorylated in MCF-7 breast cancer cells in response to epidermal growth factor (EGF), an event that enhances its DNA binding. Interestingly, treatment with alkaline phosphatase shifts ERRalpha from a dimeric to a monomeric DNA-binding factor, and only the dimeric form interacts with the coactivator PGC-1alpha. In vitro, the DNA-binding domain of ERRalpha is selectively phosphorylated by protein kinase Cdelta (PKCdelta), which increases its DNA-binding activity, whereas expression of constitutively active PKCdelta enhances TFF1 promoter activity via the ERRE. However, whereas treatment of MCF-7 cells with the phorbol ester phorbol-12-myristate 13-acetate also enhances ERRalpha activation of the TFF1 promoter reporter, it does not affect ERRalpha activity on its own promoter. In agreement, chromatin immunoprecipitation analysis shows that ERRalpha and RNA polymerase II are preferentially recruited to the TFF1 promoter after EGF treatment, whereas recruitment of these factors to its own promoter is not affected. These results reveal a mechanism through which growth factor signaling can selectively activate ERRalpha target genes in breast cancer cells.
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PMID:Epidermal growth factor-induced signaling in breast cancer cells results in selective target gene activation by orphan nuclear receptor estrogen-related receptor alpha. 1602 13

Initiation of transcription is a major point of transcriptional regulation and invariably involves the transition from a closed to an open RNA polymerase (RNAP) promoter complex. In the case of the sigma(54)-RNAP, this multi step process requires energy, provided by ATP hydrolysis occurring within the AAA+ domain of enhancer binding proteins (EBPs). Typically, EBPs have an N-terminal regulatory domain, a central AAA+ domain that directly contacts sigma(54) and a C-terminal DNA binding domain. The following AAA+ EBP crystal structures have recently become available: heptameric AAA+ domains of NtrC1 and dimeric NtrC1 with its regulatory domain, hexameric AAA+ domains of ZraR with DNA binding domains, apo and nucleotide bound forms of the AAA+ domain of PspF as well as a cryo-EM structure of the AAA+ domain of PspF complexed with sigma(54). These AAA+ domains reveal the structural conservation between EBPs and other AAA+ domains. EBP specific structural features involved in substrate remodelling are located proximal to the pore of the hexameric ring. Parallels with the substrate binding elements near the central pore of other AAA+ members are drawn. We propose a structural model of EBPs in complex with a sigma(54)-RNAP-promoter complex.
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PMID:Structures and organisation of AAA+ enhancer binding proteins in transcriptional activation. 1653 Oct 68

Helicobacter pylori is an important risk factor of gastric cancer (GC). Although many H. pylori virulence factors have been reported, the pathogenic mechanism by which H. pylori infection causes GC remains unclear. The aims of this study were to identify GC-related antigens from H. pylori and characterize their roles in the development of GC. As GC and duodenal ulcer (DU) are considered clinically divergent, we compared two-dimensional immunoblots of an acid-glycine extract of H. pylori probed with serum samples from 15 patients with GC and 15 with DU to find GC-related antigens, which were subsequently identified by mass spectrometry. Many protein spots were recognized by more than one serum, and 24 of these were better recognized by GC sera. The proteins showing higher frequency of recognition in GC group are threonine synthase, rod shape-determining protein, S-adenosylmethionine synthetase, peptide chain release factor 1, DNA-directed RNA polymerase alpha subunit, co-chaperonin GroES (monomeric and dimeric forms), response regulator OmpR, and membrane fusion protein. Of these proteins, GroES was identified as a dominant GC-related antigen with a much higher seropositivity of GC samples (64.2%, n = 95) compared with 30.9% for gastritis (n = 94) and 35.5% for DU (n = 124). GroES seropositivity was more commonly associated with antral GC than with non-antral GC (odds ratio = 2.7; 95% confidence interval, 1.1-6.7). In peripheral blood mononuclear cells, GroES stimulated production of interleukin (IL)-8, IL-6, granulocyte macrophage colony-stimulating factor, IL-1beta, tumor necrosis factor-alpha, cyclooxygenase-2, and prostaglandin E(2). Moreover when incubated with gastric epithelial cells, GroES induced expression of IL-8, cell proliferation, and up-regulation of c-jun, c-fos, and cyclin D1 but caused down-regulation of p27(Kip1). We conclude that GroES of H. pylori is a novel GC-associated virulence factor and may contribute to gastric carcinogenesis via induction of inflammation and promotion of cell proliferation.
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PMID:Comparative immunoproteomics of identification and characterization of virulence factors from Helicobacter pylori related to gastric cancer. 1676 9

Transcription activator protein C of bacteriophage Mu activates transcription of the late genes, including mom, during the lytic cycle of the phage. C binding to its site leads to the alteration in DNA topology of the promoter elements resulting in RNA polymerase (RNAP) recruitment. At the next step, the transactivator enhances promoter clearance of RNAP from P(mom). The C protein binds DNA with a very high affinity using a carboxyl-terminal helix turn helix (HTH) motif which has similarity with the HTH from paired domain of Drosophila prd protein. Previous studies established that the protein is dimeric in free and DNA bound forms. We describe now the unique dimerization interface of the protein. Two heptad repeats of hydrophobic amino acids found in the protein were considered to be the candidates for dimerization region. Site-directed mutational analysis revealed that the amino-terminal coiled coil region is not the dimerization determinant. In contrast, similar mutagenesis studies indicated a role for the leucine zipper motif, located in the middle region of the protein, in dimerization. Mixed oligomerization assays confirmed the importance of leucine zipper in C dimer formation establishing the presence of an uncommon zipper-HTH domain in the transactivator.
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PMID:Bacteriophage Mu C protein is a new member of unusual leucine zipper-HTH class of proteins. 1721 37

RNA polymerases from Archaea and Eukaryotes consist of a core enzyme associated with a dimeric E'F (Rpb7/Rpb4) subcomplex but the functional contribution of the two subunit subcomplexes to the transcription process is poorly understood. Here we report the reconstitution of the 11-subunit RNA polymerase and of the core enzyme from the hyperthermophilic Archaeon Pyrococcus furiosus. The core enzyme showed significant activity between 70 and 80 degrees C but was almost inactive at 60 degrees C. E' stimulated the activity of the core enzyme at 60 degrees C, dramatically suggesting an important role of this subunit at low growth temperatures. Subunit F did not contribute significantly to catalytic activity. Permanganate footprinting at low temperatures dissected the contributions of the core enzyme, subunit E', and of archaeal TFE to open complex formation. Opening in the -2 and -4 region could be achieved by the core enzyme, subunit E' stimulated bubble formation in general and opening at the upstream end of the transcription bubble was preferably stimulated by TFE. Analyses of the kinetic stabilities of open complexes revealed an unexpected E'-independent role of TFE in the stabilization of open complexes.
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PMID:The RPB7 orthologue E' is required for transcriptional activity of a reconstituted archaeal core enzyme at low temperatures and stimulates open complex formation. 1731 16

Craniofacial malformations, such as cleft palate, present serious complications in the newborn and are often of unknown etiology. Activin BA subunit deletion leads to cleft palate in mice, but the expression of this protein in the human palate has not been explored. Our goal was to determine the spatial and temporal expression of inhibin/activin subunits; the binding protein, follistatin; and activin receptors in the human fetal palate. Residual human fetal palate tissues, with or without cleft, were collected during routine autopsy at Women and Infants Hospital. Inhibin/activin alpha and beta subunits, follistatin, and activin receptor protein and mRNA expression were studied by immunocytochemistry and reverse-transcriptase polymerase chain reaction (RT-PCR) experiments, respectively. Dimeric activin A levels were compared in cleft and normal palate tissue homogenates by immunoassay. Activin BA, follistatin, and activin receptor type IIA proteins were observed in normal and cleft palate tissues throughout pregnancy (gestational weeks 11 to 40). Proteins were predominantly found in developing bone cells, with no significant group differences. Inhibin/activin BA subunit, follistatin, and activin receptor mRNAs were also detected in normal and cleft fetal palate tissues, but inhibin alpha and BB subunit were absent. Inhibin/activin BA subunit expression was consistent with the presence of dimeric activin A, but levels did not differ significantly between cleft and control tissues. Inhibin/activin BA subunit, follistatin, and activin receptor proteins and mRNAs are present in the human fetal palate. These data suggest that activin signalling has the potential to be associated with human palate development.
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PMID:Activin subunit and receptor expression in normal and cleft human fetal palate tissues. 1800 Nov 54

The currently circulating H3N2 and H1N1 subtypes of influenza A virus cause a transient, febrile upper respiratory illness in most adults and children ("seasonal influenza"), but infants, the elderly, immunodeficient and chronically ill persons may develop life-threatening primary viral pneumonia or complications such as bacterial pneumonia. By contrast, avian influenza viruses such as the H5N1 virus that recently emerged in Southeast Asia can cause severe disease when transferred from domestic poultry to previously healthy people ("avian influenza"). Most H5N1 patients present with fever, cough and shortness of breath that progress rapidly to adult respiratory distress syndrome. In seasonal influenza, viral replication remains confined to the respiratory tract, but limited studies indicate that H5N1 infections are characterized by systemic viral dissemination, high cytokine levels and multiorgan failure. Gastrointestinal infection and encephalitis also occur. The licensed anti-influenza drugs (the M2 ion channel blockers, amantadine and rimantadine, and the neuraminidase inhibitors, oseltamivir and zanamivir) are beneficial for uncomplicated seasonal influenza, but appropriate dosing regimens for severe seasonal or H5N1 viral infections have not been defined. Treatment options may be limited by the rapid emergence of drug-resistant viruses. Ribavirin has also been used to a limited extent to treat influenza. This article reviews licensed drugs and treatments under development, including high-dose oseltamivir; parenterally administered neuraminidase inhibitors, peramivir and zanamivir; dimeric forms of zanamivir; the RNA polymerase inhibitor T-705; a ribavirin prodrug, viramidine; polyvalent and monoclonal antibodies; and combination therapies.
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PMID:Current and future antiviral therapy of severe seasonal and avian influenza. 1832 78


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