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)

Cyclin-dependent kinases (CDKs) play key regulatory roles in diverse cellular functions, including cell-cycle progression, transcription and translation. In plants, CDKs have been classified into several groups, named A through to G, but the functions of most are poorly characterized. CDKCs are known to phosphorylate the C-terminal domain (CTD) of RNA polymerase II (RNAP II), and therefore the CDKC-cyclinT (CycT) complex may have a role similar to the animal CDK9-CycT complex of the positive transcription elongation factor b (P-TEFb). However, we found that the predicted structure of the Arabidopsis CDKC2 protein is more similar to the mammalian cdc2-related kinase, CRK7, than to CDK9. CRK7 is proposed to link transcription with splicing, and CDKC2 contains all the structural features of CRK7 that make the latter distinct from CDK9. Consistent with this, we show that GFP-CDKC2 fusion proteins co-localize with spliceosomal components, that the expression of CDKC2 modifies the location of these components, and that co-localization was dependent on the transcriptional status of the cells and on CDKC2-kinase activity. We propose, therefore, that the Arabidopsis CDKC2 combines the functions of both CRK7 and CDK9, and could also couple splicing with transcription.
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PMID:A cyclin-dependent protein kinase, CDKC2, colocalizes with and modulates the distribution of spliceosomal components in Arabidopsis. 1820 22

The positive transcription elongation factor b (P-TEFb) (CDK9/cyclin T (CycT)) promotes mRNA transcriptional elongation through phosphorylation of elongation repressors and RNA polymerase II. To understand the regulation of a transcriptional CDK by its cognate cyclin, we have determined the structures of the CDK9/CycT1 and free cyclin T2. There are distinct differences between CDK9/CycT1 and the cell cycle CDK CDK2/CycA manifested by a relative rotation of 26 degrees of CycT1 with respect to the CDK, showing for the first time plasticity in CDK cyclin interactions. The CDK9/CycT1 interface is relatively sparse but retains some core CDK-cyclin interactions. The CycT1 C-terminal helix shows flexibility that may be important for the interaction of this region with HIV TAT and HEXIM. Flavopiridol, an anticancer drug in phase II clinical trials, binds to the ATP site of CDK9 inducing unanticipated structural changes that bury the inhibitor. CDK9 activity and recognition of regulatory proteins are governed by autophosphorylation. We show that CDK9/CycT1 autophosphorylates on Thr186 in the activation segment and three C-terminal phosphorylation sites. Autophosphorylation on all sites occurs in cis.
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PMID:The structure of P-TEFb (CDK9/cyclin T1), its complex with flavopiridol and regulation by phosphorylation. 1856 85

The EBNA 2 (Epstein-Barr nuclear antigen 2) transcription factor is essential for B-cell transformation by the cancer-associated EBV (Epstein-Barr virus) and for the continuous proliferation of infected cells. EBNA 2 activates transcription from the viral Cp (C promoter) during infection to generate the 120 kb transcript that encodes all nuclear antigens required for immortalization by EBV. EBNA 2 contains an acidic activation domain and can interact with a number of general transcription factors and co-activators. It is now becoming clear, however, that the regulation of transcription elongation in addition to initiation by EBNA 2, at least in part through CDK9 (cyclin-dependent kinase 9)-dependent phosphorylation of the RNA polymerase C-terminal domain, is likely to play a crucial role in the mechanism of action of this key viral protein.
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PMID:Regulation of transcription by the Epstein-Barr virus nuclear antigen EBNA 2. 1863 Nov 29

The Positive Transcriptional Elongation Factor b (P-TEFb), a heterodimer of CDK9 and Cyclin T1, is widely implicated in control of basal gene expression. Here, P-TEFb is involved in transitioning paused RNA polymerase II to enter productive transcriptional elongation mode by phosphorylating negative elongation factors and Ser(2) of the heptad repeat in the RNA Pol II COOH terminal domain (CTD). This perspective will examine recent work in two unrelated inducible signaling pathways that illustrate the central role of P-TEFb in mediating cytokine inducible transcription networks. Specifically, P-TEFb has been recently discovered to play a key role in TNF-inducible NFkappaB activation and IL-6-inducible STAT3 signaling. In these signaling cascades, P-TEFb forms protein complexes with the activated nuclear RelA and STAT3 transcription factor in the cellular nucleoplasm, an association important for P-TEFb's promoter targeting. Studies using siRNA-mediated knockdown and/or selective CDK inhibitors show that P-TEFb plays a functional role in activation of a subset of NFkappaB-dependent targets and all STAT3-dependent genes studied to date. Interestingly, cytokine inducible genes that are sensitive to P-TEFb inhibition share an induction mechanism requiring inducible RNA Pol II recruitment. Chromatin immunoprecipitation studies have preliminarily indicated that this recruitment is dependent on CDK enzymatic activity. The potential of inhibiting P-TEFb as an anti-inflammatory therapy in innate immunity and systemic inflammation will be discussed.
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PMID:Expanding role of cyclin dependent kinases in cytokine inducible gene expression. 1872 88

Cyclin-dependent kinase 9 (Cdk9) is a cdc2-like serine/threonine kinase. The so-called Cdk9-related pathway comprises two Cdk9 isoforms (Cdk9-42 and Cdk9-55), cyclin T1, cyclin T2a, cyclin T2b and cyclin K. The association between Cdk9 and one of its cyclin partners forms a heterodimer, which is the main component of the positive transcription elongation factor (P-TEFb). The latter stabilizes the elongation process of RNA polymerase II (polII) transcripts. Through the control of RNA polII-mediated gene expression, the Cdk9-related pathway performs an important role in several biological processes, such as cell growth, proliferation, protection from apoptosis and differentiation. Incidentally, the P-TEFb that contains the heterodimer Cdk9-cyclin T1 is also critical for HIV-1 and HIV-2 replication in human cells. A deregulation in the Cdk9-related pathway is associated with various types of human malignancies and cardiomyocytes hypertrophy. On these grounds, the characterization of Cdk9-related pathway deregulation might have a two-fold purpose: (1) the development of novel kinase inhibitors for the treatment of cancer, AIDS and cardiac hypertrophy and (2) a better understanding of the pathogenesis and progression of these maladies.
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PMID:Role of the cyclin-dependent kinase 9-related pathway in mammalian gene expression and human diseases. 1902 9

Acetylation of the RelA subunit of NF-kappaB, especially at lysine-310, is critical for the transcriptional activation of NF-kappaB and the expression of inflammatory genes. In this study, we demonstrate that bromodomains of Brd4 bind to acetylated lysine-310. Brd4 enhances transcriptional activation of NF-kappaB and the expression of a subset of NF-kappaB-responsive inflammatory genes in an acetylated lysine-310-dependent manner. Bromodomains of Brd4 and acetylated lysine-310 of RelA are both required for the mutual interaction and coactivation function of Brd4. Finally, we demonstrate that Brd4 further recruits CDK9 to phosphorylate C-terminal domain of RNA polymerase II and facilitate the transcription of NF-kappaB-dependent inflammatory genes. Our results identify Brd4 as a novel coactivator of NF-kappaB through specifically binding to acetylated lysine-310 of RelA. In addition, these studies reveal a mechanism by which acetylated RelA stimulates the transcriptional activity of NF-kappaB and the NF-kappaB-dependent inflammatory response.
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PMID:Brd4 coactivates transcriptional activation of NF-kappaB via specific binding to acetylated RelA. 1910 49

Eukaryotic transcription by RNA polymerase II is a highly regulated process and divided into three major steps: initiation, elongation, and termination. Each step of transcription is controlled by a number of cellular factors. Positive transcription factor b, P-TEFb, is composed of cyclin-dependent kinase 9 and a regulatory cyclin (T1/T2). P-TEFb promotes transcriptional elongation of RNA polymerase II by using the catalytic function of CDK9 to phosphorylate various substrates during transcription. P-TEFb is inactivated by sequestration in a complex with the Hexim1 protein and 7SK RNA. The structure of this inactive P-TEFb complex and the mechanisms controlling its equilibrium with the active complex are poorly understood. Here, we used a photoactive nucleotide, 4-thioU, to study the interactions between 7SK RNA and Hexim1. We identified a specific cross-link between nucleotide U30 of 7SK RNA and amino acids 210-220 of Hexim1, in the context of both a minimal RNA-binding site and a fully reconstituted 7SK/Hexim1/P-TEFb ribonucleoprotein complex. We show also that a minimal 7SK RNA hairpin comprising nucleotides 24-87 can bind specifically to Hexim1 in vivo. Our results demonstrate directly that the Hexim1 binding site is located in the 24-87 region of 7SK RNA and that the protein residues outside the basic domain of Hexim1 are involved in specific RNA interactions.
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PMID:U30 of 7SK RNA forms a specific photo-cross-link with Hexim1 in the context of both a minimal RNA-binding site and a fully reconstituted 7SK/Hexim1/P-TEFb ribonucleoprotein complex. 1924 21

Inhibitors of cyclin-dependent kinases (CDKs) undergoing clinical trials as anticancer agents usually target several CDKs in cells. Some of them are also able to increase cellular levels of p53 protein and to activate p53-regulated transcription. To define the role of p53 in the anticancer effect of selective CDK inhibitors, two related compounds roscovitine and olomoucine II were studied. Roscovitine differs functionally from its congener olomoucine II only in the selectivity towards transcriptional CDK9. Action of both compounds on proliferation, cell-cycle progression, and apoptosis was examined in RPMI-8226 cells expressing the temperature-sensitive mutant of p53 and in MCF-7 cells with wild-type p53. Both compounds blocked proliferation, decreased phosphorylation of RNA polymerase II, downregulated antiapoptotic protein Mcl-1 in both cell lines in a dose-dependent manner, and also activated p53 in MCF-7 cells. Moreover, we showed that the anticancer efficiency of CDK inhibitors was enhanced by active p53 in RPMI-8226 cells kept at permissive temperature, where downregulation of Mcl-1, fragmentation of PARP-1, and increased caspase-3 activity was detected with lower doses of the compounds. The results confirm that functional p53 protein may enhance the anticancer activity of roscovitine that could be beneficial for anticancer therapy.
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PMID:Functional p53 in cells contributes to the anticancer effect of the cyclin-dependent kinase inhibitor roscovitine. 1930 36

The elongation competence of the RNA polymerase II complex is critically dependent on the positive transcription elongation factor b (P-TEFb). P-TEFb exists in two forms in cells, an active form composed of cyclin T1 and CDK9 and an inactive form, in which cyclin T1/CDK9 is sequestered by Hexim1 and 7SK snRNA. Here, we report that partitioning of active and inactive P-TEFb is regulated by acetylation of cyclin T1. Cyclin T1 acetylation triggers dissociation of Hexim1 and 7SK snRNA from cyclin T1/CDK9 and activates the transcriptional activity of P-TEFb. This activation is lost in P-TEFb complexes containing cyclin T1 that can no longer be acetylated. An acetylation-deficient cyclin T1 mutant dominantly suppresses NF-kappaB-mediated activation of the interleukin-8 promoter but continues to synergize normally with the HIV Tat protein to transactivate the HIV long terminal repeat. These findings support the model that acetylation of cyclin T1 serves as a physiological switch that liberates P-TEFb from its endogenous inhibitors Hexim1 and 7SK snRNA, but is not required for the cooperative action with HIV Tat.
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PMID:Acetylation of cyclin T1 regulates the equilibrium between active and inactive P-TEFb in cells. 1938 90

Post-translational histone modifications have essential roles in controlling nuclear processes; however, the specific mechanisms regulating these modifications and their combinatorial activities remain elusive. Cyclin-dependent kinase 9 (CDK9) regulates gene expression by phosphorylating transcriptional regulatory proteins, including the RNA polymerase II carboxy-terminal domain. Here, we show that CDK9 activity is essential for maintaining global and gene-associated levels of histone H2B monoubiquitination (H2Bub1). Furthermore, CDK9 activity and H2Bub1 help to maintain correct replication-dependent histone messenger RNA (mRNA) 3'-end processing. CDK9 knockdown consistently resulted in inefficient recognition of the correct mRNA 3'-end cleavage site and led to increased read-through of RNA polymerase II to an alternative downstream polyadenylation signal. Thus, CDK9 acts to integrate phosphorylation during transcription with chromatin modifications to control co-transcriptional histone mRNA processing.
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PMID:CDK9 directs H2B monoubiquitination and controls replication-dependent histone mRNA 3'-end processing. 1957 11


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