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Query: UNIPROT:P23193 (transcription elongation factor)
 739 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chromatin structure exerts vital control over gene expression, DNA replication, recombination, and repair. In addition to altering RNA polymerase II's (Pol II) accessibility to DNA, histones are involved in the recruitment of activator and repressor complex(es) to regulate gene expression. Histone deacetylase Rpd3 exists in two distinct forms, Rpd3S and Rpd3L. Several recent studies demonstrated that the Eaf3 chromodomain, an Rpd3S subunit, recognizes Set2-methylated histone H3K36, initiating Rpd3 deacetylase activity in the wake of transcribing Pol II. Eaf3 and Set2 inhibit internal initiation within mRNA coding regions, similar to the transcription elongation factor and histone chaperone, FACT. Recent studies reviewed here demonstrate that histone deacetylation on the body of a transcribed gene is regulated via Set2-mediated methylation of histone H3-K36. These modifications provide restoration of normal chromatin structure in the wake of elongating Pol II and prevent inappropriate initiation within protein-coding regions masked by chromatin.
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PMID:A site to remember: H3K36 methylation a mark for histone deacetylation. 1734 57

Myc forms an heterodimer with Max and operates as a transcription factor upon binding to specific DNA sites in cellular chromatin. In addition to recruit histone acetylation activity, Myc binds to the positive transcription elongation factor b (P-TEFb) which consists of the cyclin-dependent kinase CKD9 and its regulatory subunit cyclin T. P-TEFb phosphorylates the carboxyl-terminal-domain (CTD) of the larger subunit of RNA polymerase II as well as negative elongation factors allowing efficient transcription elongation. Here, we report that Myc binds, as heterodimer with Max, exclusively the core active P-TEFb complex, and it recruits P-TEFb at Myc targets in vivo. Pharmacological inhibition of P-TEFb by 5.6-di-chloro-1-b-D-ribofuranosyl-bensimidazole (DRB) specifically inhibits expression of Myc-responsive CAD and NUC genes, and impairs the Myc-induced S-phase and apoptosis of quiescent cells grown in low serum. Chromatin immunoprecipitation assays (ChIP) demonstrated co-occupancy of Myc and P-TEFb to CAD and NUC E-boxes, and DRB treatment diminished the density of Pol II phosphorylated on Ser-2 of its CTD. These results indicate that P-TEFb is recruited in vivo to Myc-target promoters and CDK9 activity is an important step for Myc-dependent stimulation of responsive genes.
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PMID:P-TEFb is a crucial co-factor for Myc transactivation. 1770 62

In this article, we provide direct evidence that the evolutionarily conserved transcription elongation factor TFIIS functions during preinitiation complex assembly. First, we identified TFIIS in a mass spectrometric screen of RNA polymerase II (Pol II) preinitiation complexes (PICs). Second, we show that the association of TFIIS with a promoter depends on functional PIC components including Mediator and the SAGA complex. Third, we demonstrate that TFIIS is required for efficient formation of active PICs. Using truncation mutants of TFIIS, we find that the Pol II-binding domain is the minimal domain necessary to stimulate PIC assembly. However, efficient formation of active PICs requires both the Pol II-binding domain and the poorly understood N-terminal domain. Importantly, Domain III, which is required for the elongation function of TFIIS, is dispensable during PIC assembly. The results demonstrate that TFIIS is a PIC component that is required for efficient formation and/or stability of the complex.
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PMID:The transcription elongation factor TFIIS is a component of RNA polymerase II preinitiation complexes. 1791 84

Positive transcription elongation factor b (P-TEFb) is the major metazoan RNA polymerase II (Pol II) carboxyl-terminal domain (CTD) Ser2 kinase, and its activity is believed to promote productive elongation and coupled RNA processing. Here, we demonstrate that P-TEFb is critical for the transition of Pol II into a mature transcription elongation complex in vivo. Within 3 min following P-TEFb inhibition, most polymerases were restricted to within 150 bp of the transcription initiation site of the active Drosophila melanogaster Hsp70 gene, and live-cell imaging demonstrated that these polymerases were stably associated. Polymerases already productively elongating at the time of P-TEFb inhibition, however, proceeded with elongation in the absence of active P-TEFb and cleared from the Hsp70 gene. Strikingly, all transcription factors tested (P-TEFb, Spt5, Spt6, and TFIIS) and RNA-processing factor CstF50 exited the body of the gene with kinetics indistinguishable from that of Pol II. An analysis of the phosphorylation state of Pol II upon the inhibition of P-TEFb also revealed no detectable CTD Ser2 phosphatase activity upstream of the Hsp70 polyadenylation site. In the continued presence of P-TEFb inhibitor, Pol II levels across the gene eventually recovered.
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PMID:P-TEFb is critical for the maturation of RNA polymerase II into productive elongation in vivo. 1807 Sep 27

The positive elongation factor P-TEFb appears to function as a crucial C-terminal-domain (CTD) kinase for RNA polymerase II (Pol II) transcribing immediate early genes (IEGs) in neuroendocrine GH4C1 cells. Chromatin immunoprecipitation indicated that in resting cells Pol II occupied the promoter-proximal regions of the c-fos and junB genes, together with the negative elongation factors DSIF and NELF. Thyrotropin-releasing hormone (TRH)-induced recruitment of positive transcription elongation factor b (P-TEFb) abolished the pausing of Pol II and enhanced phosphorylation of CTD serine 2, resulting in transcription elongation. In addition, P-TEFb was essential for splicing and 3'-end processing of IEG transcripts. Importantly, the MEK1-extracellular signal-regulated kinase (ERK) signaling pathway activated by TRH up-regulated nuclear CDK9 and CDK9/cyclinT1 dimers (i.e., P-TEFb), facilitating the recruitment of P-TEFb to c-fos and other IEGs. Thus, in addition to established gene transcription control via promoter response elements, the MEK1-ERK signaling pathway controls transcription elongation by Pol II via the up-regulation of nuclear CDK9 integrated into P-TEFb.
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PMID:Up-regulation of P-TEFb by the MEK1-extracellular signal-regulated kinase signaling pathway contributes to stimulated transcription elongation of immediate early genes in neuroendocrine cells. 1808 94

Phosphorylation of the C-terminal domain (CTD) of the largest subunit of RNA polymerase II (Pol II) regulates transcription cycle and coordinates recruitment of RNA processing factors and chromatin regulators. Recently, we reported the identification of human PCIF1 as a novel protein that directly binds to the phosphorylated CTD via its WW domain, which is highly homologous to the WW domain of human peptidylprolyl isomerase Pin1. Although PCIF1 has been shown to associate with phosphorylated Pol II, functional consequence of the interaction remains unclear. Here we further characterized the cytological, structural, and functional properties of human PCIF1. Immunofluorescence microscopy revealed that endogenous PCIF1 was colocalized with the phosphorylated Pol II and the transcription elongation factor DSIF in the cell nucleus. We also found that PCIF1 WW domain inhibits the CTD phosphatase activity of SCP1 in vitro. By examining the effect of either PCIF1 overexpression or knockdown on the transactivation of reporter gene expression by various transcriptional activation domains, we found that PCIF1 significantly repressed the transactivation depend on its CTD binding ability. These data suggest that PCIF1 modulates phosphorylation status of the CTD and negatively regulates gene expression by Pol II.
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PMID:Human phosphorylated CTD-interacting protein, PCIF1, negatively modulates gene expression by RNA polymerase II. 1829 53

NF-kappaB plays a central role in cytokine-inducible inflammatory gene expression. Previously we empirically determined the identity of 92 members of the genetic network under direct NF-kappaB/RelA control that show marked heterogeneity in magnitude of transcriptional induction and kinetics of peak activation. To investigate this network further, we have applied a recently developed two-step chromatin immunoprecipitation assay that accurately reflects association and disassociation of RelA binding to its chromatin targets. Although inducible RelA binding occurs with similar kinetics on all NF-kappaB-dependent genes, serine 276 (Ser(276))-phosphorylated RelA binding is seen primarily on a subset of genes that are rapidly induced by tumor necrosis factor (TNF), including Gro-beta, interleukin-8 (IL-8), and IkappaBalpha. Previous work has shown that TNF-inducible RelA Ser(276) phosphorylation is controlled by a reactive oxygen species (ROS)-protein kinase A signaling pathway. To further understand the role of phospho-Ser(276) RelA in target gene expression, we inhibited its formation by ROS scavengers and antioxidants, treatments that disrupt phospho-Ser(276) formation but not the translocation and DNA binding of nonphosphorylated RelA. Here we find that phospho-Ser(276) RelA is required only for activation of IL-8 and Gro-beta, with IkappaBalpha being unaffected. These data were confirmed in experiments using RelA(-/-) murine embryonic fibroblasts reconstituted with a RelA Ser(276)Ala mutation. In addition, we observe that phospho-Ser(276) RelA binds the positive transcription elongation factor b (P-TEFb), a complex containing the cyclin-dependent kinase 9 (CDK-9) and cyclin T1 subunits. Inhibition of P-TEFb activity by short interfering RNA (siRNA)-mediated knockdown shows that the phospho-Ser(276) RelA-P-TEFb complex is required for IL-8 and Gro-beta gene activation but not for IkappaBalpha gene activation. These studies indicate that TNF induces target gene expression by heterogeneous mechanisms. One is mediated by phospho-Ser(276) RelA formation and chromatin targeting of P-TEFb controlling polymerase II (Pol II) recruitment and carboxy-terminal domain phosphorylation on the IL-8 and Gro-beta genes. The second involves a phospho-Ser(276) RelA-independent activation of genes preloaded with Pol II, exemplified by the IkappaBalpha gene. Together, these data suggest that the binding kinetics, selection of genomic targets, and mechanisms of promoter induction by RelA are controlled by a phosphorylation code influencing its interactions with coactivators and transcriptional elongation factors.
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PMID:RelA Ser276 phosphorylation is required for activation of a subset of NF-kappaB-dependent genes by recruiting cyclin-dependent kinase 9/cyclin T1 complexes. 1836 69

Hexamethylene bis-acetamide-inducible protein 1 (HEXIM1) was identified earlier as an inhibitor of positive transcription elongation factor b (P-TEFb), which is a key transcriptional regulator of RNA polymerase II (Pol II). Studies show that more than half of P-TEFb in cells is associated with HEXIM1, which results in the inactivation of P-TEFb. Here, we identify a nucleolar protein, nucleophosmin (NPM), as a HEXIM1-binding protein. NPM binds to HEXIM1 in vitro and in vivo, and functions as a negative regulator of HEXIM1. Over-expression of NPM leads to proteasome-mediated degradation of HEXIM1, resulting in activation of P-TEFb-dependent transcription. In contrast, an increase in HEXIM1 protein levels and a decrease in transcription are detected when NPM is knocked down. We show that a cytoplasmic mutant of NPM, NPMc+, associates with and sequesters HEXIM1 in the cytoplasm resulting in higher RNA Pol II transcription. Correspondingly, cytoplasmic localization of endogenous HEXIM1 is detected in an acute myeloid leukemia (AML) cell line containing the NPMc+ mutation, suggesting the physiological importance of HEXIM1-NPMc+ interaction. Over-expression of NPM has been detected in tumors of various histological origins and our results may provide a possible molecular mechanism for the proto-oncogenic function of NPM. Furthermore, considering that 35% of AML patients are diagnosed with NPMc+ mutation, our findings suggest that in some cases of AML, RNA Pol II transcription may be disregulated by the malfunction of NPM and the mislocation of HEXIM1.
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PMID:Nucleophosmin interacts with HEXIM1 and regulates RNA polymerase II transcription. 1837 77

The family of Cyclin-Dependent Kinases (CDKs) can be subdivided into two major functional groups based on their roles in cell cycle and/or transcriptional control. CDK9 is the catalytic subunit of positive transcription elongation factor b (P-TEFb). CDK9 is the kinase of the TAK complex (Tat-associated kinase complex), and binds to Tat protein of HIV, suggesting a possible role for CDK9 in AIDS progression. CDK9 complexed with its regulatory partner cyclin T1, serves as a cellular mediator of the transactivation function of the HIV Tat protein. P-TEFb is responsible for the phosphorylation of the carboxyl-terminal domain of RNA Pol II, resulting in stimulation of transcription. Furthermore, the complexes containing CDK9 induce the differentiation in distinct tissue. The CDK9/cyclin T1 complex is expressed at higher level in more differentiated primary neuroectodermal and neuroblastoma tumors, showing a correlation between the kinase expression and tumor differentiation grade. This may have clinical and therapeutical implications for these tumor types. Among the CDK inhibitors two have shown to be effective against CDK9: Roscovitine and Flavopiridol. These two inhibitors prevented the replication of human immunodeficiency virus (HIV) type 1 by blocking Tat transactivation of the HIV type 1 promoter. These compounds inhibit CDKs by binding to the catalytic domain in place of ATP, preventing transfer of a phosphate group to the substrate. More sensitive therapeutic agents of CDK9 can be designed, and structural studies can add information in the understanding of this kinase. The major features related to CDK9 inhibition will be reviewed in this article.
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PMID:CDK9 a potential target for drug development. 1847 13

TFIIS is a transcription elongation factor that stimulates transcript cleavage activity of arrested RNA polymerase II (Pol II). Recent studies revealed that TFIIS has also a role in Pol II transcription initiation. To improve our understanding of TFIIS function in vivo, we performed genome-wide location analysis of this factor. Under normal growth conditions, TFIIS was detected on Pol II-transcribed genes, and TFIIS occupancy was well correlated with that of Pol II, indicating that TFIIS recruitment is not restricted to NTP-depleted cells. Unexpectedly, TFIIS was also detected on almost all Pol III-transcribed genes. TFIIS and Pol III occupancies correlated well genome-wide on this novel class of targets. In vivo, some dst1 mutants were partly defective in tRNA synthesis and showed a reduced Pol III occupancy at the restrictive temperature. In vitro transcription assays suggested that TFIIS may affect Pol III start site selection. These data provide strong in vivo and in vitro evidence in favor of a role of TFIIS as a general Pol III transcription factor.
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PMID:Genome-wide location analysis reveals a role of TFIIS in RNA polymerase III transcription. 1862 99


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