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)

Modulation of the activity of the upstream binding factor (UBF) plays a key role in cell cycle-dependent regulation of rRNA synthesis. Activation of rDNA transcription on serum stimulation requires phosphorylation of UBF at serine 484 by G(1)-specific cyclin-dependent kinase (cdk)/cyclin complexes. After G(1) progression UBF is phosphorylated at serine 388 by cdk2/cyclin E and cdk2/cyclin A. Conversion of serine 388 to glycine abolishes UBF activity, whereas substitution by aspartate enhances the transactivating function of UBF. Protein-protein interaction studies reveal that phosphorylation at serine 388 is required for the interaction between RNA polymerase I and UBF. The results suggest that phosphorylation of UBF represents a powerful means of modulating the assembly of the transcription initiation complex in a proliferation- and cell cycle-dependent fashion.
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PMID:Phosphorylation of UBF at serine 388 is required for interaction with RNA polymerase I and activation of rDNA transcription. 1169 41

Although the PITSLRE protein kinases are members of the cyclin-dependent kinase superfamily, their cellular function is unclear. Previously we demonstrated that the general RNA splicing factor RNPS1 is a specific PITSLRE p110 kinase interactor in vivo. This suggests that the PITSLRE family of protein kinases is involved in some aspect of RNA processing or transcription. Here we identify multiple transcriptional elongation factors, including ELL2, TFIIF(1), TFIIS, and FACT, as PITSLRE kinase-associated proteins. We demonstrate that PITSLRE p110 protein kinases co-immunoprecipitate and/or co-purify with these elongation factors as well as with RNA polymerase II. Antibody-mediated inhibition of PITSLRE kinase specifically suppressed RNA polymerase II-dependent in vitro transcription initiated at a GC-rich (adenosine deaminase) or TATA box-dependent (Ad2ML) promoter, and this suppression was rescued by readdition of purified PITSLRE p110 kinase. Together, these data strongly suggest that PITSLRE protein kinases participate in a signaling pathway that potentially regulates or links transcription and RNA processing events.
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PMID:PITSLRE p110 protein kinases associate with transcription complexes and affect their activity. 1170 59

The carboxyl-terminal domain (CTD) of the largest subunit of mammalian RNA polymerase II (RNAP II) consists of 52 repeats of a consensus heptapeptide and is subject to phosphorylation and dephosphorylation events during each round of transcription. RNAP II activity is regulated during the cell cycle and cell cycle-dependend changes in RNAP II activity correlate well with CTD phosphorylation. In addition, global changes in the CTD phosphorylation status are observed in response to mitogenic or cytostatic signals such as growth factors, mitogens and DNA-damaging agents. Several CTD kinases are members of the cyclin-dependent kinase (CDK) superfamily and associate with transcription initiation complexes. Other CTD kinases implicated in cell cycle regulation include the mitogen-activated protein kinases ERK-1/2 and the c-Abl tyrosine kinase. These observations suggest that reversible RNAP II CTD phosphorylation may play a key role in linking cell cycle regulatory events to coordinated changes in transcription.
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PMID:Regulation of RNA polymerase II activity by CTD phosphorylation and cell cycle control. 1180 20

Basal transcription factor TFIIH phosphorylates the RNA polymerase II (RNApII) carboxy-terminal domain (CTD) within the transcription initiation complex. The catalytic kinase subunit of TFIIH is a member of the cyclin-dependent kinase (Cdk) family, designated Kin28 in Saccharomyces cerevisiae and Cdk7 in higher eukaryotes. Together with TFIIH subunits cyclin H and Mat1, Cdk7 kinase is also found in a trimer complex known as Cdk activating kinase (CAK). A yeast trimer complex has not previously been identified, although a Kin28-Ccl1 dimer called TFIIK has been isolated as a breakdown product of TFIIH. Here we show that a trimeric complex of Kin28-Ccl1-Tfb3 exists in yeast extracts. Several Kin28 point mutants that are defective in CTD phosphorylation were created. Consistent with earlier studies, these mutants have no transcriptional defect in vitro. Like other Cdks, Kin28 is activated by phosphorylation on T162 of the T loop. Kin28 T162 mutants have no growth defects alone but do demonstrate synthetic phenotypes when combined with mutant versions of the cyclin partner, Ccl1. Surprisingly, these phosphorylation site mutants appear to destabilize the association of the cyclin subunit within the context of TFIIH but not within the trimer complex.
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PMID:Kin28 is found within TFIIH and a Kin28-Ccl1-Tfb3 trimer complex with differential sensitivities to T-loop phosphorylation. 1183 96

CDK7 is a cyclin-dependent kinase proposed to function in two essential cellular processes: transcription and cell cycle regulation. CDK7 is the kinase subunit of the general transcription factor TFIIH that phosphorylates the C-terminal domain (CTD) of RNA polymerase II, and has been shown to be broadly required for transcription in Saccharomyces cerevisiae. CDK7 can also phosphorylate CDKs that promote cell cycle progression, and has been shown to function as a CDK-activating kinase (CAK) in Schizosaccharomyces pombe and Drosophila melanogaster. That CDK7 performs both functions in metazoans has been difficult to prove because transcription is essential for cell cycle progression in most cells. We have isolated a temperature-sensitive mutation in Caenorhabditis elegans cdk-7 and have used it to analyze the role of cdk-7 in embryonic blastomeres, where cell cycle progression is independent of transcription. Partial loss of cdk-7 activity leads to a general decrease in CTD phosphorylation and embryonic transcription, and severe loss of cdk-7 activity blocks all cell divisions. Our results support a dual role for metazoan CDK7 as a broadly required CTD kinase, and as a CAK essential for cell cycle progression.
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PMID:cdk-7 Is required for mRNA transcription and cell cycle progression in Caenorhabditis elegans embryos. 1196 10

The PITSLRE protein kinases, hereafter referred to as cyclin-dependent kinase 11 (CDK11) due to their association with cyclin L, are part of large molecular weight protein complexes that contain RNA polymerase II (RNAP II) as well as numerous transcription and RNA processing factors. Data presented here demonstrate that the influence of CDK11(p110) on transcription and splicing does not involve phosphorylation of the RNAP II carboxyl-terminal domain by CDK11(p110). We have isolated a DRB- and heparin-sensitive protein kinase activity that co-purifies with CDK11(p110) after ion exchange and affinity purification chromatography. This protein kinase was identified as casein kinase 2 (CK2) by immunoblot and mass spectrometry analyses. In addition to the RNAP II carboxyl-terminal domain, CK2 phosphorylates the CDK11(p110) amino-terminal domain. These data suggest that CDK11(p110) isoforms participate in signaling pathways that include CK2 and that its function may help to coordinate the regulation of RNA transcription and processing events. Future experiments will determine how phosphorylation of CDK11(p110) by CK2 specifically affects RNA transcription and/or processing events.
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PMID:Casein kinase 2 interacts with cyclin-dependent kinase 11 (CDK11) in vivo and phosphorylates both the RNA polymerase II carboxyl-terminal domain and CDK11 in vitro. 1242 41

The budding yeast Saccharomyces cerevisiae differentiates into filamentous invasively growing forms under conditions of nutrient limitation. This response is dependent on the transcription factor Ste12 and on the mating pheromone-response mitogen-activated protein (MAP) kinase cascade, but a mechanism for regulation of Ste12 by nutrient limitation has not been defined. Here we show that Ste12 function in filamentous growth is regulated by the cyclin-dependent kinase Srb10 (also known as Cdk8), which is associated with the RNA polymerase II holoenzyme. Srb10 inhibits filamentous growth in cells growing in rich medium by phosphorylating Ste12 and decreasing its stability. Under conditions of limiting nitrogen, loss of Srb10 protein and kinase activity occurs, with a corresponding loss of Ste12 phosphorylation. Mutation of the Srb10-dependent phosphorylation sites increases pseudohyphal development but has no effect on the pheromone response of haploid yeast. Srb10 kinase activity is also regulated independently of the mating pheromone-response pathway. This indicates that Srb10 controls Ste12 activity for filamentous growth in response to nitrogen limitation and is consistent with the hypothesis that Srb10 regulates gene-specific activators in response to physiological signals to coordinate gene expression with growth potential.
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PMID:Srb10/Cdk8 regulates yeast filamentous growth by phosphorylating the transcription factor Ste12. 1252 Mar 6

Activation of cyclin-dependent kinases (CDKs) requires phosphorylation of a threonine residue within the T-loop by a CDK-activating kinase (CAK). Here we isolated an Arabidopsis cDNA (CAK4At) whose predicted product shows a high similarity to vertebrate CDK7/p40(MO15). Northern blot analysis showed that expressions of the four Arabidopsis CAKs (CAK1At-CAK4At) were not dependent on cell division. CAK2At- and CAK4At-immunoprecipitates of Arabidopsis crude extract phosphorylated CDK and the carboxy-terminal domain (CTD) of the largest subunit of RNA polymerase II with different preferences. These results suggest the existence of differential mechanisms in Arabidopsis that control CDK and CTD phosphorylation by multiple CAKs.
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PMID:Differential phosphorylation activities of CDK-activating kinases in Arabidopsis thaliana. 1252 63

During mitosis, the cyclin-dependent kinase, Cdc2, signals the inactivation of major anabolic processes such as transcription, mRNA processing, translation, and ribosome biogenesis, thereby providing energy needed for the radical and energetically costly structural reorganization of the cell. This is accomplished by phosphorylation and inactivation of several key anabolic elements, including TFIIIB, TFIID, RNA polymerase II, poly(A) polymerase, and translation elongation factor 1gamma. We report here that ribosomal S6 kinase 1 (S6K1), a protein kinase linked to the translation of ribosomal protein mRNAs, is also subject to regulation by Cdc2 in mitosis. In mitotic HeLa cells, when the activity of Cdc2 is high, S6K1 is phosphorylated at multiple Ser/Thr, Pro (S/TP) sites, including Ser(371), Ser(411), Thr(421), and Ser(424). Concomitant with this, the phosphorylation of the hydrophobic motif site, Thr(389), is reduced resulting in a decrease in the specific activity of S6K1. The mitotic S/TP phosphorylation sites are readily phosphorylated by Cdc2.cyclin B in vitro. These proline-directed phosphorylations are sensitive to chemical inhibitors of Cdc2 but not to inhibitors of mammalian target of rapamycin, phosphatidylinositol 3-kinase, MEK1/2, or p38. In murine FT210 cells arrested in mitosis, conditional inactivation of Cdc2 reduces phosphorylation of S6K1 at S/TP sites while simultaneously increasing phosphorylation of Thr(389) and of the S6K1 substrate, RPS6. A physical interaction exists between Cdc2 and S6K1, and this interaction is enhanced in mitotic cells. These results suggest that Cdc2 provides a signal that triggers inactivation of S6K1 in mitosis, presumably serving to spare energy for costly mitotic processes at the expense of ribosomal protein synthesis.
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PMID:Mitotic regulation of ribosomal S6 kinase 1 involves Ser/Thr, Pro phosphorylation of consensus and non-consensus sites by Cdc2. 1258 35

Positive transcription factor b (P-TEFb) is required for RNA polymerase II to make the transition from abortive to productive elongation. This important factor is a heterodimer of a cyclin-dependent kinase, cyclin-dependent kinase 9 (Cdk9), and one of four cyclin partners, cyclin T1, T2a, T2b or K. We demonstrate here that there exists in cells a second form of Cdk9 that is 13 kDa larger than the protein originally identified. Both of these forms, which we name Cdk9(42) and Cdk9(55), are present in HeLa and NIH/3T3 cells. Cdk9(55) is generated from an mRNA that originates from a second promoter located upstream of the startpoint of transcription used to generate mRNAs encoding Cdk9(42). Antibodies specific for Cdk9(55) immunoprecipitate Cdk(55) and cyclin T1, but not Cdk9(42). Cdk9(55) in the immunoprecipitates is active as judged by its ability to phosphorylate the carboxyl-terminal domain of the largest subunit of RNA polymerase II. Recently it has been shown that the activity of P-TEFb is negatively regulated in cells by reversible association with a small cellular RNA called 7SK. We show here that P-TEFb molecules containing either form of Cdk9 are found in association with 7SK and both complexes are disrupted by treatment with 600 mM KCl. The relative abundance of Cdk9(55) and Cdk9(42) changes in different cell types, including HeLa, NIH/3T3, human macrophages and mouse lung tissue. Additionally, treatment of macrophages with lipopolysaccharides or infection with human immunodeficiency virus alters the relative abundance of the two forms of Cdk9.
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PMID:Identification of a novel isoform of Cdk9. 1270


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