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)

A novel human complex that can either repress activator-dependent transcription mediated by PC4, or, at limiting TFIIH, act synergistically with PC4 to enhance activator-dependent transcription has been purified. This complex contains homologs of a subset of yeast mediator/holoenzyme components (including SRB7, SRB10, SRB11, MED6, and RGR1), homologs of other yeast transcriptional regulatory factors (SOH1 and NUT2), and, significantly, some components (TRAP220, TRAP170/hRGR1, and TRAP100) of a human thyroid hormone receptor-associated coactivator complex. The complex shows direct activator interactions but, unlike yeast mediator, can act independently of the RNA polymerase II CTD. These findings demonstrate both positive and negative functional capabilities for the human complex, emphasize novel (CTD-independent) regulatory mechanisms, and link the complex to other human coactivator complexes.
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PMID:A novel human SRB/MED-containing cofactor complex, SMCC, involved in transcription regulation. 1002 83

The human thyroid hormone receptor-associated protein (TRAP) complex, an earlier described coactivator for nuclear receptors, and an SRB- and MED-containing cofactor complex (SMCC) that mediates activation by Gal4-p53 are shown to be virtually the same with respect to specific polypeptide subunits, coactivator functions, and mechanisms of action (activator interactions). In parallel with ligand-dependent interactions of nuclear receptors with the TRAP220 subunit, p53 and VP16 activation domains interact directly with a newly cloned TRAP80 subunit. These results indicate novel pathways for the function of nuclear receptors and other activators (p53 and VP16) through a common coactivator complex that is likely to target RNA polymerase II. Identification of the TRAP230 subunit as a previously predicted gene product also suggests a coactivator-related transcription defect in certain disease states.
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PMID:Identity between TRAP and SMCC complexes indicates novel pathways for the function of nuclear receptors and diverse mammalian activators. 1019 38

Structures of yeast Mediator complex, of a related complex from mouse cells and of thyroid hormone receptor-associated protein complex from human cells have been determined by three-dimensional reconstruction from electron micrographs of single particles. All three complexes show a division in two parts, a "head" domain and a combined "middle-tail" domain. The head domains of the three complexes appear most similar and interact most closely with RNA polymerase II. The middle-tail domains show the greatest structural divergence and, in the case of the tail domain, may not interact with polymerase at all. Consistent with this structural divergence, analysis of a yeast Mediator mutant localizes subunits that are not conserved between yeast and mammalian cells to the tail domain. Biochemically defined Rgr1 and Srb4 modules of yeast Mediator are then assigned to the middle and head domains.
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PMID:Structural organization of yeast and mammalian mediator complexes. 1111 91

The multisubunit TRAP/Mediator complex is a mammalian counterpart of the yeast Mediator that shows diverse coactivation functions. Genetic ablation of the murine TRAP100 component of this complex has revealed that it is not essential for cell viability per se. However, null mutant mice die at an early developmental stage with severe malformations, and cultured TRAP100-deficient cells exhibit attenuated functions of a wide variety of transcriptional activators on ectopic reporters. The TRAP100-deficient TRAP/Mediator complex also lacks TRAP95 and TRAP150 beta/SUR2, which together with TRAP100 may form a submodule, and contains a reduced amount of SRB10/CDK8. Nevertheless, the residual complex shows unaltered binding both to RNA polymerase II and, with the exception of the oncoprotein E1A, to various activators. These findings suggest that TRAP/Mediator is broadly involved in transcription and that a TRAP100-containing submodule plays a secondary role, beyond primary activator interactions and RNA polymerase recruitment by the TRAP complex, in magnifying effects of activators on the general transcriptional machinery.
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PMID:The TRAP100 component of the TRAP/Mediator complex is essential in broad transcriptional events and development. 1209 47

Characterization of a balanced t(2;12)(q37;q24) translocation in a patient with suspicion of Noonan syndrome revealed that the chromosome 12 breakpoint lies in the vicinity of a novel human gene, thyroid hormone receptor-associated protein 2 (THRAP2). We therefore characterized this gene and its mouse counterpart in more detail. Human and mouse THRAP2/Thrap2 span a genomic region of about 310 and >170 kilobases (kb), and both contain 31 exons. Corresponding transcripts are approximately 9.5 kb long. Their open reading frames code for proteins of 2210 and 2203 amino acids, which are 93% identical. By northern blot analysis, human and mouse THRAP2/Thrap2 genes showed ubiquitous expression. Transcripts were most abundant in human skeletal muscle and in mouse heart. THRAP2 protein is 56% identical to human TRAP240, which belongs to the thyroid hormone receptor associated protein (TRAP) complex and is evolutionary conserved up to yeast. This complex is involved in transcriptional regulation and is believed to serve as adapting interface between regulatory proteins bound to specific DNA sequences and RNA polymerase II.
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PMID:cDNA cloning and characterization of the human THRAP2 gene which maps to chromosome 12q24, and its mouse ortholog Thrap2. 1514 61

Mediator is a general coactivator complex connecting transcription activators and RNA polymerase II. Recent work has shown that the nuclear receptor-interacting MED1/TRAP220 subunit of Mediator is required for peroxisome proliferator-activated receptor gamma (PPARgamma)-stimulated adipogenesis of mouse embryonic fibroblasts (MEFs). However, the molecular mechanisms remain undefined. Here, we show an intracellular PPARgamma-Mediator interaction that requires the two LXXLL nuclear receptor recognition motifs on MED1/TRAP220 and, furthermore, we show that the intact LXXLL motifs are essential for optimal PPARgamma function in a reconstituted cell-free transcription system. Surprisingly, a conserved N-terminal region of MED1/TRAP220 that lacks the LXXLL motifs but gets incorporated into Mediator fully supports PPARgamma-stimulated adipogenesis. Moreover, in undifferentiated MEFs, MED1/TRAP220 is dispensable both for PPARgamma-mediated target gene activation and for recruitment of Mediator to a PPAR response element on the aP2 target gene promoter. However, PPARgamma shows significantly reduced transcriptional activity in cells deficient for a subunit (MED24/TRAP100) important for the integrity of the Mediator complex, indicating a general Mediator requirement for PPARgamma function. These results indicate that there is a conditional requirement for MED1/TRAP220 and that a direct interaction between PPARgamma and Mediator through MED1/TRAP220 is not essential either for PPARgamma-stimulated adipogenesis or for PPARgamma target gene expression in cultured fibroblasts. As Mediator is apparently essential for PPARgamma transcriptional activity, our data indicate the presence of alternative mechanisms for Mediator recruitment, possibly through intermediate cofactors or other cofactors that are functionally redundant with MED1/TRAP220.
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PMID:Alternative mechanisms by which mediator subunit MED1/TRAP220 regulates peroxisome proliferator-activated receptor gamma-stimulated adipogenesis and target gene expression. 1803 40

Inflammation in response to excess low-density lipoproteins in the blood is an important driver of atherosclerosis development. Due to its ability to enhance ATP-binding cassette A1-dependent (ABCA1-dependent) reverse cholesterol transport (RCT), liver X receptor (LXR) is an attractive target for the treatment of atherosclerosis. However, LXR also upregulates the expression of sterol regulatory element-binding protein 1c (SREBP-1c), leading to increased hepatic triglyceride synthesis, an independent risk factor for atherosclerosis. Here, we developed a strategy to separate the favorable and unfavorable effects of LXR by exploiting the specificity of the coactivator thyroid hormone receptor-associated protein 80 (TRAP80). Using human hepatic cell lines, we determined that TRAP80 selectively promotes the transcription of SREBP-1c but not ABCA1. Adenovirus-mediated expression of shTRAP80 inhibited LXR-dependent SREBP-1c expression and RNA polymerase II recruitment to the LXR responsive element (LXRE) of SREBP-1c, but not to the LXRE of ABCA1. In murine models, liver-specific knockdown of TRAP80 ameliorated liver steatosis and hypertriglyceridemia induced by LXR activation and maintained RCT stimulation by the LXR ligand. Together, these data indicate that TRAP80 is a selective regulator of hepatic lipogenesis and is required for LXR-dependent SREBP-1c activation. Moreover, targeting the interaction between TRAP80 and LXR should facilitate the development of potential LXR agonists that effectively prevent atherosclerosis.
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PMID:Hepatic TRAP80 selectively regulates lipogenic activity of liver X receptor. 2543 75