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)

The nucleotide sequence of a 26.7 kb DNA segment from the left arm of Saccharomyces cerevisiae chromosome IV is presented. An analysis of this segment revealed 11 open reading frames (ORFs) longer than 300 bp and one split gene. These ORFs include the genes encoding the large subunit of RNA polymerase II, the biotin apo-protein ligase, an ADP-ribosylation factor (ARF 2), the 'L35'-ribosomal protein, a rho GDP dissociation factor, and the sequence encoding the protein phosphatase 2A. Further sequence analysis revealed a short ORF encoding the ribosomal protein YL41B, an intron in a 5' untranslated region and an extended homology with another cosmid (X83276) located on the same chromosome. The potential biological relevance of these findings is discussed.
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PMID:Analysis of a 26,756 bp segment from the left arm of yeast chromosome IV. 897 77

Growth-dependent regulation of rRNA synthesis is mediated by TIF-IA, a basal transcription initiation factor for RNA polymerase I. We inactivated the murine TIF-IA gene by homologous recombination in mice and embryonic fibroblasts (MEFs). TIF-IA-/- embryos die before or at embryonic day 9.5 (E9.5), displaying retardation of growth and development. In MEFs, Cre-mediated depletion of TIF-IA leads to disruption of nucleoli, cell cycle arrest, upregulation of p53, and induction of apoptosis. Elevated levels of p53 after TIF-IA depletion are due to increased binding of ribosomal proteins, such as L11, to MDM2 and decreased interaction of MDM2 with p53 and p19(ARF). RNAi-induced loss of p53 overcomes proliferation arrest and apoptosis in response to TIF-IA ablation. The striking correlation between perturbation of nucleolar function, elevated levels of p53, and induction of cell suicide supports the view that the nucleolus is a stress sensor that regulates p53 activity.
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PMID:Genetic inactivation of the transcription factor TIF-IA leads to nucleolar disruption, cell cycle arrest, and p53-mediated apoptosis. 1598 66

RNA is now considered a key factor in the regulation of gene expression. There are several classes of small regulatory RNAs in plants, functioning in posttranscriptional gene silencing (PTGS) or epigenetic DNA modification. Trans-acting short interfering RNAs (tasiRNAs) form a class of small regulatory RNAs which has been distinguished only recently. To date, five genes encoding tasiRNAs have been identified in Arabidopsis thaliana. TasiRNAs derive from non-coding RNA precursors which are initially targeted for cleavage by a miRNA. Cleavage products are then converted into dsRNAs by a RNA dependent RNA polymerase and sequentially cleaved into 21-nt tasiRNAs. Like the majority of plant miRNAs, tasiRNAs regulate gene expression at the posttranscriptional level, guiding cleavage of ARF and PPR transcripts. Here, we briefly present tasiRNAs and speculate whether they form a homogeneous class of siRNAs.
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PMID:[Trans-acting short interfering RNAs]. 1720 Oct 60

The tumour suppressor protein ARF provides a defence mechanism against hyperproliferative stresses that can result from the aberrant activation of oncogenes. Accordingly, ARF is silenced or deleted in many human cancers. Activation of ARF can arrest growth and cell cycle progression, or trigger apoptosis. A principle mediator of these effects is p53, which ARF stabilizes by binding and inhibiting MDM2. However, ARF has additional targets and remains able to block growth in the absence of p53, albeit less efficiently. For example, ARF can suppress rRNA production in a p53-independent manner. We have found that the synthesis of tRNA by RNA polymerase III is also inhibited in response to ARF. However, in contrast to its effects on rRNA synthesis, ARF is unable to inhibit tRNA gene transcription when p53 is ablated. These results add to the growing list of cellular changes that can be triggered by ARF induction.
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PMID:RNA polymerase III transcription is repressed in response to the tumour suppressor ARF. 1743 68

RNA polymerase III (RNA pol III) transcribes many small structural RNA molecules involved in RNA processing and translation, and thus regulates the growth rate of a cell. Accurate initiation by RNA pol III requires the initiation factor TFIIIB. TFIIIB has been demonstrated to be regulated by tumor suppressors, including ARF, p53, RB, and the RB-related pocket proteins, and is a target of the oncogene c-myc and the mitogen-activated protein kinase ERK. EGCG has been demonstrated to inhibit the growth of a variety of cancer cells, induce apoptosis and regulate the expression of p53, myc, and ERK. Thus, we hypothesized that EGCG may regulate RNA pol III transcription in cells. Here, we report that EGCG (1) inhibits RNA pol III transcription from gene internal and gene external promoters (2) EGCG inhibits protein expression of the TFIIIB subunits Brf1 and Brf2, and (3) EGCG inhibits Brf2 promoter activity in cervical carcinoma cells.
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PMID:The green tea component EGCG inhibits RNA polymerase III transcription. 1762 4

More than 20 genes in the Arabidopsis genome encode proteins similar to phosphatases that act on the carboxyl-terminal domain (CTD) of RNA polymerase II. One of these CTD-phosphatase-like (CPL) proteins, CPL2, dephosphorylates CTD-Ser5-PO4 in an intact RNA polymerase II complex and contains a double-stranded (ds)-RNA-binding motif (DRM). Although the dsRNA-binding activity of CPL2 DRM has not been shown to date, T-DNA insertion mutants that express CPL2 variants lacking either a part of DRM (cpl2-1) or the entire DRM (cpl2-2) exhibited leaf expansion defects, early flowering, low fertility, and increased salt sensitivity. cpl2 mutant plants produced shorter hypocotyls than wild-type plants in the light, but were indistinguishable from wild type in the dark. CPL2 was expressed in shoot and root meristems and vasculatures, expanding rosette leaves, and floral organs suggesting a focal role for growth. Microarray and RT-PCR analyses revealed that basal levels of several auxin-responsive transcripts were reduced in cpl2. On the other hand, the levels of endogenous auxin and its conjugates were similar in wild type and cpl2. Overexpression of ARF5 but not all activator ARF transcription factors restored the auxin-responsive DR5-GUS reporter gene expression and the leaf expansion of cpl2 mutant plants but not early flowering phenotype. These results establish CPL2 as a multifunctional regulator that modulates plant growth, stress, and auxin responses.
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PMID:The Arabidopsis thaliana carboxyl-terminal domain phosphatase-like 2 regulates plant growth, stress and auxin responses. 1850 80

RNA polymerase III (RNA pol III) transcribes structural RNAs involved in RNA processing (U6 snRNA) and translation (tRNA), thereby regulating the growth rate of cells. Proper initiation by RNA pol III requires the transcription factor TFIIIB. Gene-external U6 snRNA transcription requires TFIIIB consisting of Bdp1, TBP, and Brf2. Transcription from the gene-internal tRNA promoter requires TFIIIB composed of Bdp1, TBP, and Brf1. TFIIIB is a target of tumor suppressors, including PTEN, ARF, p53, and RB, and RB-related pocket proteins. Breast cancer susceptibility gene 1 (BRCA1) tumor suppressor plays a role in DNA repair, cell cycle regulation, apoptosis, genome integrity, and ubiquitination. BRCA1 has a conserved amino-terminal RING domain, an activation domain 1 (AD1), and an acidic carboxyl-terminal domain (BRCA1 C-terminal region). In Saccharomyces cerevisiae, TFIIB interacts with the BRCA1 C-terminal region domain of Fcp1p, an RNA polymerase II phosphatase. The TFIIIB subunits Brf1 and Brf2 are structurally similar to TFIIB. Hence, we hypothesize that RNA pol III may be regulated by BRCA1 via the TFIIB family members Brf1 and Brf2. Here we report that: (1) BRCA1 inhibits both VAI (tRNA) and U6 snRNA RNA pol III transcription; (2) the AD1 of BRCA1 is responsible for inhibition of U6 snRNA transcription, whereas the RING domain and AD1 of BRCA1 are required for VAI transcription inhibition; and (3) overexpression of Brf1 and Brf2 alleviates inhibition of U6 snRNA and VAI transcription by BRCA1. Taken together, these data suggest that BRCA1 is a general repressor of RNA pol III transcription.
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PMID:Inhibition of RNA polymerase III transcription by BRCA1. 1936 18

The p14/p19(ARF) (ARF) product of the CDKN2A gene displays tumor suppressor activity both in the presence and absence of p53/TP53. In p53-negative cells, ARF arrests cell proliferation, at least in part, by suppressing ribosomal RNA synthesis. We show that ARF does this by controlling the subnuclear localization of the RNA polymerase I transcription termination factor, TTF-I. TTF-I shuttles between nucleoplasm and nucleolus with the aid of the chaperone NPM/B23 and a nucleolar localization sequence within its N-terminal regulatory domain. ARF inhibits nucleolar import of TTF-I by binding to this nucleolar localization sequence, causing the accumulation of TTF-I in the nucleoplasm. Depletion of TTF-I recapitulates the effects of ARF on ribosomal RNA synthesis and is rescued by the introduction of a TTF-I transgene. Thus, our data delineate the pathway by which ARF regulates ribosomal RNA synthesis and provide a compelling explanation for the role of NPM.
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PMID:The ARF tumor suppressor controls ribosome biogenesis by regulating the RNA polymerase I transcription factor TTF-I. 2051 29

PROBLEM STATEMENT: RNA polymerase III (RNA pol III) is responsible for transcribing many of the small structural RNA molecules involved in RNA processing and protein translation, thereby regulating the growth rate of a cell. RNA pol III transcribes both gene internal (tRNA) and gene external (U6 snRNA) promoters and proper initiation by RNA polymerase III requires the transcription initiation factor TFIIIB. TFIIIB has been shown to be a target of repression by tumor suppressors such as ARF, p53, RB and the RB-related pocket proteins. Also, TFIIIB activity is stimulated by the oncogenes c-Myc and the ERK mitogen-activated protein kinase. Recently, two TFIIIB subunits, BRF1 and BRF2, have been demonstrated to behave as oncogenes, making deregulation of TFIIIB activity and thus RNA pol III transcription an important step in tumor development. PTEN is a commonly mutated tumor suppressor regulating cell growth, proliferation and survival. Thus, we sought to examine the potential role of PTEN in regulating U6 snRNA transcription. APPROACH: We examined the potential for PTEN to regulate U6 snRNA transcription using in vitro RNA pol III luciferase assays, western blotting and deletion analysis in cancer cell lines differing in their PTEN status. RESULTS: Using breast, cervical, prostate and glioblastoma cancer cells we demonstrate: (1) PTEN inhibition of gene external RNA pol III transcription is cell type specific, (2) PTEN-mediated inhibition of U6 transcription occurs via the C2 lipid-binding domain and (3) PTEN repression of U6 transcription occurs, at least in part, through the TFIIIB subunit BRF2. CONCLUSION/RECOMMENDATIONS: Our data demonstrates that regulation of the U6 snRNA gene by PTEN is mediated, in part by the TFIIIB oncogene BRF2, potentially identifying novel targets for chemotherapeutic drug design.
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PMID:Inhibition of U6 snRNA Transcription by PTEN. 2147 60

The transcription factor c-Myc has a critical role in cell proliferation and growth. The control of ribosome biogenesis by c-Myc through the regulation of transcription mediated by all three RNA polymerases is essential for c-Myc-driven proliferation. Specifically, in the nucleolus, c-Myc has been shown to be recruited to ribosomal DNA and activate RNA polymerase (pol) I-mediated transcription of ribosomal RNA (rRNA) genes. In addition, c-Myc accumulates in nucleoli upon inhibition of the proteasome, suggesting nucleolar localization also has a role in c-Myc proteolysis. Nucleophosmin (NPM), a predominantly nucleolar protein, is also critical in ribosome biogenesis and, like c-Myc, is found overexpressed in many types of tumors. Previously, we demonstrated that NPM directly interacts with c-Myc and controls c-Myc-induced hyperproliferation and transformation. Here, we show that NPM is necessary for the localization of c-Myc protein to nucleoli, whereas c-Myc nucleolar localization is independent of p53, Mdm2 and ARF. Conversely, high transient NPM expression enhances c-Myc nucleolar localization, leading to increased c-Myc proteolysis. In addition, NPM is necessary for the ability of c-Myc to induce rRNA synthesis in the nucleolus, and constitutive NPM overexpression stimulates c-Myc-mediated rRNA synthesis. Taken together, these results demonstrate an essential role for NPM in c-Myc nucleolar localization and c-Myc-mediated rDNA transcription.
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PMID:Nucleophosmin is essential for c-Myc nucleolar localization and c-Myc-mediated rDNA transcription. 2266 62


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