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 tumor suppressor protein p53 is frequently inactivated in tumors. It functions as a transcriptional activator as well as a repressor for a number of viral and cellular promoters transcribed by RNA polymerase II (Pol II) and by RNA Pol III. Moreover, it appears that p53 also suppresses RNA Pol I transcription. In this study, we examined the molecular mechanism of Pol I transcriptional inhibition by p53. We show that wild-type, but not mutant, p53 can repress Pol I transcription from a human rRNA gene promoter in cotransfection assays. Furthermore, we show that recombinant p53 inhibits rRNA transcription in a cell-free transcription system. In agreement with these results, p53-null epithelial cells display an increased Pol I transcriptional activity compared to that of epithelial cells that express p53. However, both cell lines display comparable Pol I factor protein levels. Our biochemical analysis shows that p53 prevents the interaction between SL1 and UBF. Protein-protein interaction assays indicate that p53 binds to SL1, and this interaction is mostly mediated by direct contacts with TATA-binding protein and TAF(I)110. Moreover, template commitment assays show that while the formation of a UBF-SL1 complex can partially relieve the inhibition of transcription, only the assembly of a UBF-SL1-Pol I initiation complex on the rDNA promoter confers substantial protection against p53 inhibition. In summary, our results suggest that p53 represses RNA Pol I transcription by directly interfering with the assembly of a productive transcriptional machinery on the rRNA promoter.
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PMID:Repression of RNA polymerase I transcription by the tumor suppressor p53. 1091 76

Germline mutations of BRCA1 predispose women to breast and ovarian cancers. BRCA1 contains several functional domains that interact directly or indirectly with a variety of molecules, including tumor suppressors (p53, RB, BRCA2 and ATM), oncogenes (c-Myc, casein kinase II and E2F), DNA damage repair proteins (RAD50 and RAD51), cell-cycle regulators (cyclins and cyclin-dependent kinases), transcriptional activators and repressors (RNA polymerase II, RHA, histone deacetylase complex and CtIP) and others. Mounting evidence indicates that these physical associations are not artifacts; rather, BRCA1 is likely to serve as an important central component in multiple biological pathways that regulate cell-cycle progression, centrosome duplication, DNA damage repair, cell growth and apoptosis, and transcriptional activation and repression. This review examines our understanding of the significance of the interactions between BRCA1 and other proteins, through which BRCA1 maintains genome integrity and represses tumor formation. Published 2000 John Wiley & Sons, Inc.
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PMID:Roles of BRCA1 and its interacting proteins. 1091 3

Disruption of the function of tumor suppressor proteins occasionally can be dependent on their subcellular localization. In about 40% of the breast cancer tissues, p53 is found in the cytoplasm as opposed to the nucleus, where it resides in normal breast cells. This means that the regulation of subcellular location of p53 is an important mechanism in controlling its function. The transport factors required for the nuclear export of p53 and the mechanisms of their nuclear export have been extensively characterized. However, little is known about the mechanism of nuclear import of p53. p53 contains putative nuclear localization signals (NLSs) which would interact with a nuclear transport factor, importin alpha. In this report we demonstrate that importin alpha binds to NLSI in p53 and mediates the nuclear import of p53. Reverse transcriptase-polymerase chain reaction and sequencing analyses showed that a truncated importin alpha deleted the region encoding the putative NLS-binding domain of p53, suggesting that it could not bind to NLSs of p53 proteins. Binding of importin alpha to p53 was confirmed by using yeast two-hybrid assay. When expressed in CHO-K1 cells, the truncated importin alpha predominantly localized to the cytoplasm. In truncated importin alpha expressing cells, p53 preferentially localized to cytoplasmic sites as well. A significant increase in the p21(waf1/cip1) mRNA level and induction of apoptosis were also observed in importin alpha overexpressing cells. These results strongly suggest that importin alpha functions as a component of the NLS receptor for p53 and mediates nuclear import of p53.
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PMID:Truncated form of importin alpha identified in breast cancer cell inhibits nuclear import of p53. 1093 Apr 27

We have previously suggested that the inhibition of RNA polymerase II-mediated transcription after exposure to UV light promotes the accumulation of p53 and the induction of apoptosis (Oncogene 13, 823-831). However, it was not clear whether p53 induction was contributing to apoptosis. Here we report that apoptosis is triggered at lower UV doses in p53-deficient Li-Fraumeni syndrome (LFS) and human papillomavirus (HPV) E6 expressing fibroblasts than in normal cells, suggesting that p53 can be protective against UV-induced apoptosis. There is no significant difference in the effect of UV-irradiation on the cell cycle distribution of normal and primary LFS fibroblasts. Importantly, the recovery of nascent mRNA synthesis in all p53-deficient fibroblasts is significantly impaired compared with control cells after exposure to relevant doses of UV light. Taken together, our results suggest that wild-type p53 can protect cells against UV-induced apoptosis by facilitating the recovery of transcription. Furthermore, we suggest that the capacity of cells to recover transcription after genotoxic damage is an important determinant of sensitivity to apoptosis.
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PMID:Role for p53 in the recovery of transcription and protection against apoptosis induced by ultraviolet light. 1093 82

DNA-dependent protein kinase (DNA-PK) is involved in DNA repair but there is some evidence to suggest that it is also involved in regulating transcription. We used a pair of cell lines, SCVA2 and SC(8)-10, which are DNA-PK negative and positive respectively, in order to examine the effect of DNA-PK upon transcription. Initial experiments were performed using p53 as an activator of transcription because DNA-PK has been proposed as a candidate upstream activator of p53. It was found both in vivo and in vitro that efficient p53-dependent transcription required the presence of DNA-PK. However, phosphorylation of p53 by DNA-PK did not affect the DNA-binding ability of p53 nor its transcriptional activity when tested in vitro. Subsequent in vivo experiments suggested that a number of transcription activators functioned more efficiently in the presence of DNA-PK. Therefore DNA-PK may play a general role in regulation of transcription driven by RNA polymerase II. In addition, DNA-PK is shown to have no specific effect on p53-dependent transcription.
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PMID:Transcription by RNA polymerase II in DNA-PK deficient scid mouse cells. 1097 5

The transcriptional mechanism of Borna disease virus (BDV) has been poorly understood. We have analyzed transcription of the virus upon various stimuli in Madin-Darby canine kidney cells which were persistently infected by BDV (MDCK/BDV). Treatment with actinomycin D (ActD) increased the level of BDV RNA, shifting the size of RNA from 1.9 kb to 2.3 kb beginning 5 hr after the treatment. To understand the mechanism of this unique modulation of BDV RNA, we conducted several experiments. The RNA increase occurred at the stage in which synthesis of cellular intrinsic mRNA was intact, suggesting BDV does not compete with cellular transcriptional machinery for intrinsic RNA polymerase II. The BDV transcription was also enhanced by cycloheximide treatment, indicating that newly synthesized viral or cellular proteins are not necessary for viral transcription. However, a shift in the RNA size was not observed for cycloheximide-induced BDV RNA. The increase in viral transcription persisted during the cellular apoptotic process consequent to p53 gene accumulation beginning 1 hr after ActD treatment. Caspase inhibitors Z-VAD and DEVD-CHO repressed the apoptotic process but failed to block the increase in BDV transcription. In addition, adenovirus-mediated transduction of wild-type p53 did not alter the BDV transcription, indicating that the increase in BDV transcription was independent of the p53-mediated apoptotic process. Other various stimuli that evoke cellular signal transductions failed to alter BDV transcription. Agents inhibitory to topoisomerase except adriamycin failed to enhance BDV transcription, indicating that the increase in BDV transcription is not mediated by an inhibitory action to the topoisomerase II of ActD. Adriamycin showed an increase and size-shift of BDV RNA similar to ActD. These results suggest that intercalation of the viral genome itself with ActD is related to the stabilization of viral RNA and alteration of RNA size rather than secondary host cell changes.
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PMID:The mechanism of actinomycin D-mediated increase of Borna disease virus (BDV) RNA in cells persistently infected by BDV. 1098 33

The level of RNA polymerase (pol) III transcription is tightly linked to the rate of growth; it is low in resting cells and increases following mitogenic stimulation. When mammalian cells begin to proliferate, maximal pol III activity is reached shortly before the G1/S transition; it then remains high throughout S and G2 phases. Recent data suggest that the retinoblastoma protein RB and its relatives p107 and p130 may be largely responsible for this pattern of expression. During G0 and early G1 phase, RB and p130 bind and repress the pol III-specific factor TFIIIB; shortly before S phase they dissociate from TFIIIB, allowing transcription to increase. At the end of interphase, when cells enter mitosis, pol III transcription is again suppressed; this mitotic repression is achieved through direct phosphorylation of TFIIIB. Thus, pol III transcription levels fluctuate as mammalian cells cycle, being high in S and G2 phases and low during mitosis and early G1. In addition to this cyclic regulation, TFIIIB can be bound and repressed by the tumor suppressor p53. Conversely, it is a target for activation by several viruses, including SV40, HBV, and HTLV-1. Some viruses also increase the activity of a second pol III-specific factor called TFIIIC. A large proportion of transformed and tumor cell types express abnormally high levels of pol III products. This may be explained, at least in part, by the very high frequency with which RB and p53 become inactivated during neoplastic transformation; loss of function of these cardinal tumor suppressors may release TFIIIB from key restraints that operate in normal cells.
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PMID:RNA polymerase III transcription: its control by tumor suppressors and its deregulation by transforming agents. 1109 22

It has been hypothesized that the degradation of the largest subunit of RNA polymerase II (polIILS) is required for transcription-coupled repair (TCR) of UV light-induced transcription-blocking lesions. In this study we further investigated the mechanism of UV-induced degradation of polIILS using cell lines with specific defects in TCR or in the recovery of RNA synthesis. It was found that the hypophosphorylated IIa form of polIILS rapidly decreased following UV-irradiation in all cell lines tested. Inhibition of proteasome activity resulted in an increase of the hyperphosphorylated IIo form of polIILS in UV-irradiated cells, while inhibition of CTD-kinases resulted in the retention of the IIa form. In UV-irradiated Cockayne's syndrome cells, which are defective in TCR, the levels of the IIo form increased in a similar manner as when proteasome inhibitors were added to UV-irradiated normal cells. In contrast, TCR-deficient HCT116 cells, which lack the mismatch repair protein MLH1, showed proficient degradation of polIILS as did cells with deficiencies in the recovery of RNA synthesis following UV-irradiation due to defective p53. Furthermore, we found that proteasome function was important for the recovery of mRNA synthesis even in TCR-deficient HCT116 cells. Our results suggest that proteasome-mediated degradation of polIILS is preceded by phosphorylation of the C-terminal domain of polIILS and requires the CS-A and CS-B but not MLH1 or p53 proteins. Furthermore, our results suggest that following UV-irradiation, the degradation of polIILS is required for the efficient recovery of mRNA synthesis but not for TCR per se.
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PMID:UV light-induced degradation of RNA polymerase II is dependent on the Cockayne's syndrome A and B proteins but not p53 or MLH1. 1118 41

RNA polymerase III (Pol III) synthesizes various small RNA species, including the tRNAs and the 5 S ribosomal RNA, which are involved in protein synthesis. Here, we describe the regulation of human Pol III transcription in response to sustained cell cycle arrest. The experimental system used is a cell line in which cell cycle arrest is induced by the regulated expression of the tumor suppressor protein p53. We show that the capacity of cells to carry out Pol III transcription from various promoter types, when tested in vitro, is severely reduced in response to sustained p53-mediated cell cycle arrest. Furthermore, this effect does not appear to be due to direct inhibition by p53. By using complementation assays, we demonstrate that a subcomponent of the Pol III transcription factor IIIB, which contains the proteins TATA-binding protein and TAF3B2, is the target of repression. Moreover, we reveal that TAF3B2 levels are markedly reduced in extracts from cell cycle-arrested cells because of a decrease in TAF3B2 protein stability. These findings provide a novel mechanism of Pol III regulation and yield insights into how cellular biosynthetic capacity and growth status can be coordinated.
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PMID:A role for TAF3B2 in the repression of human RNA polymerase III transcription in nonproliferating cells. 1128 26

The human homolog of KET, p63, bears strong homology to the tumor suppressor p53 and plays an essential role in epithelial development. CUSP, the most abundant cutaneous product of p63, has been identified as an autoantigen in chronic ulcerative stomatitis (CUS). The original report of KET expression at least partially contradicts p63 expression subsequently reported by many different groups. We have examined p63 expression by Northern analysis of RNA from multiple human tissues and by indirect immunofluorescence of rat tissue with CUS patient sera. Northern analysis reveals p63 RNA in skin, thymus, placenta, skeletal muscle, kidney, and lung, with non-transactivating p63 RNA in skin, thymus, and placenta. Reverse transcriptase polymerase chain reaction (rtPCR) assays show abundant non-transactivating p63 RNA, and little to no transactivating p63 RNA, in human basal cell carcinoma as well as in normal skin adjacent to the tumors. p63 RNA expression was not detected in brain, heart, colon, spleen, liver, or small intestine. Immunofluorescence reveals p63 expression in skin, oral epithelium, tongue, kidney, and trachea, but not in liver, large intestine, testis, skeletal muscle, or heart. Focal p63 expression within tissues, the complex array of isoforms encoded by the gene, and the specificity of the probes and antibodies utilized, may all contribute to contradictory accounts of CUSP/p63 expression.
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PMID:CUSP/p63 expression in rat and human tissues. 1153 71


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