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)

Our understanding of how vitamin D mediates biological responses has entered a new era. It is now clear that the bulk of the biological responses supported by vitamin D occur as a consequence of its metabolism to its daughter metabolite 1 alpha,25-dihydroxyvitamin D3 (a steroid hormone). The fact that 1,25(OH)2D3 receptors are ubiquitous in tissue distribution opens the possibility for unforeseen biological functions of the vitamin D endocrine system. For example, 1,25(OH)2D3 serves as an immunoregulatory hormone and a differentiation hormone besides its classical role in mineral homeostasis. The avian 1,25)OH)2D3 receptor has recently been cloned and shown to be a member of the nuclear transacting receptor family that includes estrogen, progesterone, glucocorticoid, thyroxine (T3), aldosterone, and retinoic acid receptors. We have compiled an extensive number of RNA polymerase II-transcribed genes that are regulated by 1,25(OH)2D3. Classification of these genes on functional grounds identifies and formulates the several genetic circuits or biochemical systems in which 1,25(OH)2D3 plays an essential regulatory role. These systems include genes that govern oncogene and lymphokine expression as well as those involved in mineral homeostasis, vitamin D metabolism, and regulation of a set of replication-linked genes (c-myc, c-myb, and histone H4), which are critical for rapid cellular proliferation. An integrated analysis of the combinations of genetic circuits regulated by 1,25(OH)2D3 suggests that they may be collectively tied to a DNA replication-differentiation switch.
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PMID:1,25(OH)2-vitamin D3 receptors: gene regulation and genetic circuitry. 284 48

We present a detailed analysis of strand-specific transcription in different regions of the murine c-myc locus. In normal and transformed cell lines, RNA polymerase II directed transcription occurs in the sense and anti-sense direction. Three noncontiguous regions show a high level of transcription in the anti-sense orientation: upstream of the first exon, within the first intron and in the 3' part of the gene (intron 2 and exon 3). In a cell line carrying a c-myc amplification (54c12), anti-sense transcription is not uniformly increased throughout the locus and is differentially affected by inhibition of protein synthesis. These results suggest that anti-sense transcription in various parts of the locus is independently regulated. In the sense orientation, transcriptional activity is higher in the first exon than in the rest of the gene indicating that transcription pauses near the 3' end of the first exon. The extent of this intragenic pausing varies among different cell lines and is most severe in cells with a c-myc amplification. Transcription initiation and pausing are both negatively regulated by labile proteins.
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PMID:Intragenic pausing and anti-sense transcription within the murine c-myc locus. 302 65

We have studied transcription elongation and termination in the human c-myc gene. Transcription of c-myc gene sequences with purified mammalian RNA polymerase II revealed several sites of transcription termination and pausing in the vicinity of the exon 1-intron 1 junction. This region previously has been shown to block transcription elongation in vivo by nuclear run-on analysis (D. Bentley and M. Groudine, Nature [London] 321:702-706, 1986). These sites were recognized by purified RNA polymerase II, and we therefore designated them intrinsic sites of termination and pausing. Two of these sites cause termination of RNA polymerase III transcription as well. RNA polymerase II terminated transcription in a cluster of seven consecutive T residues in the nontranscribed strand and paused during transcription at three additional sites in this region. The intrinsic sites of transcription termination and pausing described here correspond closely to the 3' ends of transcripts synthesized in Xenopus oocytes injected with plasmids containing the c-myc termination region (D. Bentley and M. Groudine, Cell 53:245-256, 1988). This correspondence suggests that the intrinsic recognition of these termination and pause sites by purified RNA polymerase II may play a role in the transcription elongation block observed in vivo.
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PMID:Intrinsic sites of transcription termination and pausing in the c-myc gene. 305 17

To gain further insight into the mechanism of age-associated loss of T cell proliferative responses to mitogenic lectins, we measured c-myc specific mRNA accumulation in Con A-stimulated cultures of spleen cells from old and young mice using Northern blot and S1 nuclease protection analyses. Aging led to a consistent decline (an average of approximately 60%) in the level of c-myc mRNA in stimulated cells. The time course for c-myc RNA accumulation was similar for old and young mice. Nuclear runoff experiments showed that mitogen stimulation leads to an equivalent increase in transcription of the c-myc gene in T cells from old and young mice. Furthermore, in the presence of 5,6-dichlorobenzimidazole riboside, a selective inhibitor of RNA polymerase II, c-myc mRNA decayed with equal kinetics in cells from mice of different ages. These results show that lymphocytes from aged mice exhibit defects in gene expression very early in the activation process and suggest that these deficits may involve, at least for some genes, alterations in post-transcriptional processing.
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PMID:Defective T lymphocytes in old mice. Diminished production of mature c-myc RNA after mitogen exposure not attributable to alterations in transcription or RNA stability. 328 Jun 82

We have previously shown by affinity chromatography that RAP30 and RAP74 are the mammalian proteins that have the highest affinity for RNA polymerase II. Here we show that RAP30 binds to RAP74 and that the RAP30-RAP74 complex (RAP30/74) is required for accurate initiation by RNA polymerase II. RAP30/74 is required for accurate transcription from the following promoters: the adenovirus major late promoter, the long terminal repeat of human immunodeficiency virus, P2 of the human c-myc gene, the mouse beta maj-globin promoter (all of which have TATA boxes), and the mouse dihydrofolate reductase promoter (which lacks a TATA box). RAP30/74 is not required for initiation by RNA polymerase III at the adenovirus virus-associated RNA promoters. Therefore, RAP30/74 is a general initiation factor that binds to RNA polymerase II.
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PMID:RAP30/74: a general initiation factor that binds to RNA polymerase II. 338 90

We examine the influence of the immunoglobulin locus on the expression of the translocated c-myc oncogene in mouse plasmacytomas. The level of c-myc RNA was 30- 35-fold greater in tumor cells than in normal, quiescent B cells. Mitogen stimulation of the lymphocytes with lipopolysaccharide induced a 15-fold increase in c-myc expression per cell to a level that was similar to that in the transcription of the translocated c-myc gene involved initiation from sequences in the first c-myc intron. Abundant RNA transcripts were also found from the noncoding strand of the c-myc intron in most tumor lines. S1 nuclease mapping was used to locate the intronic sequences that are used to initiate the tumor-specific c-myc RNAs. Six different initiation sites within the intron were mapped, none of which have the TATA sequence usually associated with eucaryotic RNA polymerase II promoters. The noncoding strand transcripts were also found to initiate in the c-myc intron. Transcription of the c-myc coding strand was independent of the position of the translocation breakpoint, even when the heavy chain switch and constant regions were deleted.
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PMID:Transcriptional activation of the translocated c-myc oncogene in mouse plasmacytomas: similar RNA levels in tumor and proliferating normal cells. 632 72

Transcriptional activation of the c-myc proto-oncogene is mediated by the transition of promoter proximal, paused RNA polymerase II (pol II) into a processive transcription mode. Using a transcription assay which allows the high resolution mapping of transcriptional complexes in intact nuclei, we have characterized the promoter proximal pause positions of pol II. Pol II paused in a nucleosome-free region close to the transcription start site as well as further downstream, between positions +17 and +52. These pause positions were detected in both transcriptionally active and inactive c-myc genes. Pharmacological inhibition of the C-terminal phosphorylation of the large subunit of pol II did not affect the paused transcription complexes, but had an inhibitory effect on transcription of nucleosomal DNA downstream of position +150. The different properties of pol II proximal and distal to the promoter suggest a model in which c-myc transcription is regulated by the activation of promoter bound polymerases.
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PMID:Variable pause positions of RNA polymerase II lie proximal to the c-myc promoter irrespective of transcriptional activity. 756 45

IL-8 is a chemotactic cytokine with proinflammatory and growth-promoting activities. Recently it has been shown to influence several functions of keratinocytes, including HLA-DR expression, chemotaxis, and proliferation by binding to a specific receptor. Because psoriasis vulgaris is characterized by epidermal hyperproliferation and infiltration of inflammatory cells, we investigated the expression of IL-8 and its receptor in normal and psoriatic epidermis using semiquantitative reverse-transcriptase-polymerase chain reaction. In addition the mRNA levels of the proto-oncogenes c-ras, c-raf, c-myc, and HER-2 were also investigated as potential growth-promoting stimuli in psoriatic epidermis. IL-8 mRNA was only detected in lesional psoriatic epidermis, and IL-8R-specific mRNA was found to be 10 times increased in lesional psoriatic epidermis. There was no significant difference in the protooncogene mRNA levels. In order to test the relevance of the massively increased IL-8R levels in psoriatic epidermis, we investigated the effect of the antipsoriatic drug FK-506 on specific IL-8 and IL-8R mRNA expression. FK-506 dose dependently inhibited IL-8R expression and function. Our data suggest that in psoriatic skin, elevated IL-8 levels and markedly increased IL-8R expression may act in concert to induce the cardinal signs of psoriasis--epidermal hyperproliferation and leukocyte infiltration. IL-8R may prove a molecular target for antipsoriatic drugs such as FK-506.
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PMID:Increased expression of epidermal IL-8 receptor in psoriasis. Down-regulation by FK-506 in vitro. 769 48

We have shown previously that the majority of RNA polymerase II complexes initiated at the c-myc gene are paused in the promoter-proximal region, similar to observations in the Drosophila hsp70 gene. Our analyses define the TATA box or initiator sequences in the c-myc gene as necessary components for the establishment of paused RNA polymerase II. Deletion of upstream sequences or even the TATA box does not influence significantly the degree of transcriptional initiation or pausing. Deletion of both the TATA box and sequences at the transcription initiation site, however, abolishes transcriptional pausing of transcription complexes but still allows synthesis of full-length RNA. Further analyses with synthetic promoter constructs reveal that the simple combination of upstream activator with TATA consensus sequences or initiator sequences act synergistically to recruit high levels of RNA polymerase II complexes. Only a minor fraction of these complexes escapes into regions further downstream. Several different trans-activation domains fused to GAL4-DNA-binding domains, including strong activators such as VP16, do not eliminate promoter-proximal pausing of RNA polymerase. Thus, we conclude that pausing of RNA polymerase II is a common phenomenon in eukaryotic transcription and does not require complex promoter structures. Further analyses reveal that enhancers have a modest influence on transcription initiation and on release of transcription complexes out of the pause site but may function primarily to increase the elongation competence of transcription complexes.
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PMID:Promoter-proximal pausing of RNA polymerase II defines a general rate-limiting step after transcription initiation. 769 46

RNA polymerase II seems to be prone to stop at intrinsic pause sites, thus introducing a further potential level of regulation. It was recently shown that RNA polymerase II was held at the P2 promoter of c-myc gene. We confirmed the presence of engaged polymerases in the murine fibroblastic Ltk- and pre-B lymphoid 70Z3 cell lines. High resolution run-on analysis and in vivo permanganate-dependent footprinting showed that this holds true for the c-fos gene in unstimulated cells where a strong block to transcription elongation was evidenced. In contrast to what was observed in the c-myc gene, an even more intense signal was observed in run-on experiments downstream to the promoter, on a c-fos oligonucleotide including position +385 where an in vitro transcription arrest site was previously mapped. Genomic footprinting of DNA from intact cells and isolated nuclei confirmed the involvement of several thymidines belonging to a T-rich stretch in a melted region which was not detected upon polymerase release. In order to observe a short abortive c-fos transcript accumulating in vivo we resorted to microinjection of c-fos templates in Xenopus oocytes where transcripts were stable.
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PMID:Elongation and premature termination of transcripts initiated from c-fos and c-myc promoters show dissimilar patterns. 783 31


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