Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.6 (RNA polymerase)
 34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Platelet-derived growth factor (B) (PDGF(B)) from alveolar macrophages is thought to play a central role in orchestrating the fibrotic response. Because corticosteroids are widely used in the treatment of patients with lung fibrosis, we asked whether corticosteroids modulated PDGF(B) gene activation in macrophages. PDGF(B) mRNA in alveolar macrophages obtained from smokers was increased after culture in the presence of dexamethasone (P less than 0.05), interferon-gamma (IFN-gamma) (P less than 0.05), or both in combination (P less than 0.05). Dexamethasone did not alter the abundance of mRNA encoding transforming growth factor-beta (TGF-beta), but did decrease the mRNA of early growth response gene 2 (EGR2). These initial experiments required large numbers of cells and thus were performed on macrophages from smokers. The results were reproduced when PDGF(B) mRNA abundance in macrophages from healthy nonsmoking volunteers was measured by the reverse-transcriptase polymerase chain reaction (RT-PCR). There was an increase in PDGF(B) mRNA in macrophages from nonsmokers after stimulation with dexamethasone alone (P less than 0.05) or in combination with IFN-gamma (P less than 0.05). To provide adequate cell numbers for kinetic and dose-response studies, the in vitro model of phorbol ester (TPA)-induced differentiation of HL60 cells to macrophage-like cells was used. In these cells, dexamethasone caused a 20-fold increase in the abundance of PDGF(B) mRNA, which was concentration and time dependent but not associated with changes in TGF-beta or EGR2 mRNA. This study suggests that in addition to their anti-inflammatory effects, corticosteroids may also increase the abundance of PDGF(B) mRNA.
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PMID:Dexamethasone-induced increase in platelet-derived growth factor (B) mRNA in human alveolar macrophages and myelomonocytic HL60 macrophage-like cells. 149 7

The expression of genes that code for the large ribosomal RNAs (rRNAs) and tRNAs can be regulated by calcium, serum, insulin and a tumor-promoting phorbol ester, TPA. These effectors can rapidly alter rRNA and tRNA synthesis in dividing and nondividing Drosophila cells. In an in vitro assay system of the nondividing cells of the male accessory glands, calcium, insulin and TPA were shown to increase both rRNA and tRNA synthesis. Exposure of actively dividing Drosophila culture cells to differing serum concentrations or TPA also altered rRNA and tRNA synthesis. Nuclear run-on assays demonstrate that the exposure of these cells to increased serum concentrations coordinately alters RNA polymerase I loading on both 18S and 28S rDNA. These data indicate that calcium, growth factors and a tumor-promoter each can signal changes in ribosomal and tRNA gene expression.
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PMID:Serum, insulin and phorbol esters stimulate rRNA and tRNA gene expression in both dividing and nondividing Drosophila cells. 192 1

Two putative genes (termed pro 1 and pro 2) specifying sensitivity to induction of neoplastic transformation by TPA in mouse epidermal JB6 cells were cloned by sib selection from a size-selected genomic library of clonal cells sensitive to promotion of transformation. By restriction analysis, heteroduplex analysis, direct hybridization, and sequencing, the putative genes are different from and have no homology to known oncogenes. Both genes are independently and equally active as total DNA in the transfection assay. The transformation-promoting potential of these putative genes does not appear to result from gene amplification or detectable rearrangements, suggesting that small structural changes might confer the promoting activity. The mouse pro sequences are also found in monkey and human DNAs. The pro-1 sequence is homologous to middle repetitive elements in the mouse genome, namely the BAM 5 and B1 repeats. The sequence of pro-1 was determined and suggests that it contains the signals to be transcribed by RNA polymerase II and to encode a protein of 7.1 kDa.
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PMID:Cloning and characterization of putative genes that specify sensitivity to neoplastic transformation by tumor promoters. 300 90

Synovial fibroblasts from patients with osteoarthritis in culture produced parathyroid hormone-related peptide (PTHrP) on treatment with phorbol ester (TPA) in a dose- and time-dependent manner. The levels of PTHrP immunoreactivity in the conditioned medium of synovial fibroblast cultures were measured using specific PTHrP antibody. The maximum production was obtained at a concentration of 10(-8) M and 24 h after TPA treatment. But sensitivity to TPA of synovial fibroblasts differed among four patients from slight to marked. PTHrP production was also induced with inflammatory cytokines, such as 1 ng/ml of IL-1alpha, IL-1beta, IL-6 and TNF-alpha, and 10(-6) M prostaglandin E2, after 24 h treatment. The expression of PTHrP was confirmed by reverse-transcriptase polymerase chain reaction. Since the synovial fibroblasts isolated from osteoarthritic patients produce high levels of IL-6 and IL-8, typical cytokines produced in synovial fibroblasts, production of PTHrP may provide new insight into the pathophysiology of joint disorder.
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PMID:Production of parathyroid hormone-related peptide by synovial fibroblasts in human osteoarthritis. 974 21

The carboxy-terminal domain of the large subunit of mouse and human RNA polymerase II contains 52 repeats of a heptapeptide which are the targets for a variety of kinases. We have used an alpha-amanitin resistant form of the large subunit of pol II to study the role of the carboxy-terminal domain in the expression of chromosomal genes. The large subunit of RNA polymerase II and deletion mutants thereof, which contain only 31 (LSdelta31) and 5 (LSdeltaS) repeats, were expressed in 293 cells. Subsequently, the endogenous large subunit of RNA polymerase II was inhibited by alpha-amanitin and the induction of chromosomal c-fos and hsp70A genes was determined. Cells expressing the large subunit of RNA polymerase II and LSdelta31 were able to transcribe the c-fos and hsp70A genes after treatment with the phorbolester TPA and after heat-shock, respectively. In contrast, cells expressing LSdelta5 failed to induce expression of both genes.
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PMID:Requirement of the carboxy-terminal domain of RNA polymerase II for the transcriptional activation of chromosomal c-fos and hsp70A genes. 1010 Jun 37

Human herpesvirus 8 (HHV-8) has been causally linked to Kaposi's sarcoma (KS). There is significant homology between some HHV-8 genes and cellular genes including D-type cyclin (vCYC), G protein coupled receptor (vGCR), macrophage inflammatory proteins (vMIP-I, vMIP-II), bcl-2 (vBCL2), interferon regulatory factor-1 (vIRF1), interleukin-6 (vIL6), and complement-binding protein (vCBP). In this study, we analyzed expression of these viral homologs and HIV-1 Tat by reverse-transcriptase polymerase chain reaction (RT-PCR) coupled with Southern blot hybridization in AIDS-KS (AKS) tissue, classic KS tissue(CKS), and peripheral blood mononuclear cells, and phorbol ester (TPA)-treated and untreated HHV-8 positive lymphoma cells (BCBL1). While vCYC (AKS 6 of 6; CKS 3 of 3), vMIP-I (AKS 5 of 6, CKS 3 of 3), vBCL2 (AKS 6 of 6; CKS 3 of 3), and vIRF1 (AKS 5 of 6, CKS 3 of 3) transcripts were detected in both AKS and CKS, vGCR and HIV-1 Tat were expressed only in AKS samples (vGCR: AKS 3 of 6, CKS 0 of 3; Tat: AKS 4 of 6, CKS 0 of 3). vMIPII, vCBP, and vIL6 expression were not detected in any KS samples. Since vGCR expression is limited to AKS, it is possible that vGCR is activated by HIV-1 Tat. These results suggest that HIV-1 Tat may contribute to AKS pathogenesis through the tumorigenic and angiogenic effects of vGCR.
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PMID:Differential expression of the HHV-8 vGCR cellular homolog gene in AIDS-associated and classic Kaposi's sarcoma: potential role of HIV-1 Tat. 1066 20

p68 RNA helicase has been implicated in a variety of processes, including rearrangement of RNA secondary structures, RNA splicing, gene transcription and tumor development, yet its mechanisms of action are not well understood. In this study, we show that p68 is predominantly localized to the cell nucleus, where it partially colocalizes with the transcriptional coactivator p300. Accordingly, p68 and p300, or the paralogous CREB-binding protein (CBP), coimmunoprecipitate. Similarly, p68 and RNA polymerase II (Pol II) are able to interact in vivo. GST pull-down assays confirmed these interactions in vitro, demonstrating that p68 can interact with several domains of CBP, while CBP/p300 bind to amino acids 176-388 of p68 and RNA Pol II binds to the N-terminal 80 amino acids of p68. Furthermore, p68 stimulates transcription mediated by the C-terminal transactivation domain of CBP. p68 is also able to stimulate TPA oncogene responsive unit (TORU) promoter activity, and p300 acts in synergy with p68. On the other hand, suppression of CBP/p300 function by the adenoviral protein E1A abolishes TORU promoter activation by p68. Altogether, our results suggest the existence of a multiprotein complex in which p68 RNA helicase, CBP/p300 and RNA Pol II jointly promote gene expression.
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PMID:Synergism between p68 RNA helicase and the transcriptional coactivators CBP and p300. 1252 17

Receptor activator of nuclear factor (RANK) is a member of the tumor necrosis factor receptor superfamily indispensable for osteoclast differentiation. However, little is known about the regulatory mechanism of RANK expression. In the present study, RANK expression during macrophage/osteoclast differentiation was investigated using a human myelomonocytic cell line, HL60, capable of differentiating into mature osteoclasts under appropriate conditions. RANK mRNA expression was barely detectable in growing HL60 cells. We found that treatment with 1alpha,25-dihydroxyvitamin D(3) and TPA resulted in an apparent induction of RANK mRNA and protein in association with differentiation into the macrophage/osteoclast lineage. Induction of RANK was time and dose dependent and lineage specific. Moreover, RANK induction was blocked by an RNA polymerase II inhibitor, suggesting an involvement of a transcriptional mechanism. The induced RANK was functional as it was able to bind RANK ligand and activate NF-kappaB. In the induced HL60 cells expressing both c-Fms and RANK, RANK mRNA expression was further enhanced by RANKL, but not by macrophage colony-stimulating factor. These results suggest a positive feedback regulation of RANK expression by its own intracellular signaling. The in vitro system described here may be a useful model to elucidate the regulatory mechanism of RANK expression and its role in human osteoclastogenesis.
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PMID:Expression of RANK is dependent upon differentiation into the macrophage/osteoclast lineage: induction by 1alpha,25-dihydroxyvitamin D3 and TPA in a human myelomonocytic cell line, HL60. 1281 Jan 69

Recruitment of a RNA polymerase II complex by the glutamine-rich Q2 domain of cAMP response element-binding protein (CREB) allows basal transcriptional activity, while recruitment of CBP/p300 through signal-induced phosphorylation of the kinase-inducible domain at serine-133 enhances CREB-dependent transcription. Here we demonstrate that co-administration of forskolin and phorbol ester TPA to NIH3T3 cells provoked a dose-dependent increase in phosphoserine-133. CREB- and Q2-dependent transcription, as well as transcription by other glutamine-rich transcription factors, but not by transcription factors lacking glutamine-rich regions, augmented synergistically in the presence of both stimuli. Synergistic activation was abograted by specific inhibition of protein kinase C (PKC), but not of PKA. Co-stimulation increased the basal activity of a minimal, CREB-independent promoter. Therefore, Q2, which directly interacts with the RNA polymerase II initiation complex, may transmit the increased basal promoter activity provoked by these stimuli to CREB, thereby contributing to synergistic activation of CREB-mediated transcription. This synergism may have important implications on glutamine-rich transcription factor-target genes.
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PMID:Synergistic activation of CREB-mediated transcription by forskolin and phorbol ester requires PKC and depends on the glutamine-rich Q2 transactivation domain. 1524 13

Epolactaene (compound 1), a neuritogenic compound found in human neuroblastoma cells, was found to show anti-inflammatory activity in vivo in this study. DNA polymerases and DNA topoisomerase II (topo II) were some of the major molecular targets of compound 1. Since the agent seems to be a potential pharmaceutical medicine, we synthesized derivatives chemically and obtained seven compounds, 1 to 7 to screen clinically more efficient epolactaene derivatives. A comparison of its structural derivatives revealed that the long alkyl side chain seemed to have an important role in the inhibitory effect. Notably, C18-alkyl chain conjugated epolactaene (compound 5) was the strongest inhibitor of DNA polymerase alpha, beta, lambda (pol alpha, beta, lambda) and topo II, with IC50 values of 13, 135, 4.4 and 5 microM, respectively, and 500 microg of compound 5 caused a marked reduction in TPA (12-O-tetradecanoylphorbol-13-acetate)-induced inflammation (inhibitory effect, 65.0%). Compound 5 did not influence the activities of plant or prokaryotic DNA polymerases, or of other DNA metabolic enzymes such as telomerase, RNA polymerase and deoxyribonuclease I. Based on these results, the relationship among the three-dimensional structure of epolactaene derivatives and the inhibition of polymerases and topo II, and anti-inflammation is discussed.
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PMID:Structural analysis of epolactaene derivatives as DNA polymerase inhibitors and anti-inflammatory compounds. 1580 99


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