Genomes and Genes
cyclin dependent kinase 9
Summary: A multifunctional CDC2 kinase-related kinase that plays roles in transcriptional elongation, CELL DIFFERENTIATION, and APOPTOSIS. It is found associated with CYCLIN T and is a component of POSITIVE TRANSCRIPTIONAL ELONGATION FACTOR B.
- Brès V, Yoshida T, Pickle L, Jones K. SKIP interacts with c-Myc and Menin to promote HIV-1 Tat transactivation. Mol Cell. 2009;36:75-87 pubmed publisher..Thus, SKIP acts with c-Myc and Menin to promote HIV-1 Tat:P-TEFb transcription at an elongation step that is bypassed under stress. ..
- Freter R, Osawa M, Nishikawa S. Adult stem cells exhibit global suppression of RNA polymerase II serine-2 phosphorylation. Stem Cells. 2010;28:1571-80 pubmed publisher..Screening heterogeneous tissues, including tumors, for transcriptionally quiescent cells may result in the identification of cells with stem cell-like phenotypes. ..
- Cho S, Lee S, Kim Y, Park B, Choi J, Liu L, et al. Xylocydine, a novel Cdk inhibitor, is an effective inducer of apoptosis in hepatocellular carcinoma cells in vitro and in vivo. Cancer Lett. 2010;287:196-206 pubmed publisher..Taken together, these data suggest that the novel Cdk inhibitor xylocydine is a good candidate for an anti-cancer drug for HCC therapy. ..
- Koledova Z, Kafkova L, Calabkova L, Krystof V, Dolezel P, Divoky V. Cdk2 inhibition prolongs G1 phase progression in mouse embryonic stem cells. Stem Cells Dev. 2010;19:181-94 pubmed publisher..This study reveals olomoucine II to be an effective tool for manipulation of the cell cycle and pluripotency in ESCs and very likely also for the manipulation of other stem cell types, including cancer stem cells. ..
- Liu H, Herrmann C, Chiang K, Sung T, Moon S, Donehower L, et al. 55K isoform of CDK9 associates with Ku70 and is involved in DNA repair. Biochem Biophys Res Commun. 2010;397:245-50 pubmed publisher..Our findings suggest that the 55K CDK9 protein may function in repair of DNA through an association with Ku70. ..
- Zhu H, Doherty J, Kuliyev E, Mead P. CDK9/cyclin complexes modulate endoderm induction by direct interaction with Mix.3/mixer. Dev Dyn. 2009;238:1346-57 pubmed publisher..3 during embryonic development. Developmental Dynamics 238:1346-1357, 2009. (c) 2009 Wiley-Liss, Inc. ..
- Lolli G. Binding to DNA of the RNA-polymerase II C-terminal domain allows discrimination between Cdk7 and Cdk9 phosphorylation. Nucleic Acids Res. 2009;37:1260-8 pubmed publisher..CTD dissociates from DNA following phosphorylation by Cdk7, allowing transcription initiation. The CTD then becomes accessible for further phosphorylation by Cdk9 that drives the transition to transcription elongation. ..
- Takaya T, Ono K, Kawamura T, Takanabe R, Kaichi S, Morimoto T, et al. MicroRNA-1 and MicroRNA-133 in spontaneous myocardial differentiation of mouse embryonic stem cells. Circ J. 2009;73:1492-7 pubmed..miR-1 and miR-133 may play significant roles in the myocardial differentiation of mouse ES cells, and Cdk9 may be involved in this process as a target of miR-1. ..
- Tong W, Chen R, Plunkett W, Siegel D, Sinha R, Harvey R, et al. Phase I and pharmacologic study of SNS-032, a potent and selective Cdk2, 7, and 9 inhibitor, in patients with advanced chronic lymphocytic leukemia and multiple myeloma. J Clin Oncol. 2010;28:3015-22 pubmed publisher..Further single-agent, PD-based, dose and schedule modification is warranted to maximize clinical efficacy. ..
- Cho S, Schroeder S, Kaehlcke K, Kwon H, Pedal A, Herker E, et al. Acetylation of cyclin T1 regulates the equilibrium between active and inactive P-TEFb in cells. EMBO J. 2009;28:1407-17 pubmed publisher..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. ..
- Chopra V, Hong J, Levine M. Regulation of Hox gene activity by transcriptional elongation in Drosophila. Curr Biol. 2009;19:688-93 pubmed publisher..Stalled Pol II persists in tissues where Ubx and Abd-B are silenced by the PcG complex. We propose that stalling fosters both the rapid induction and precise silencing of Hox gene expression during development. ..
- Mueller D, Garcia Cuellar M, Bach C, Buhl S, Maethner E, Slany R. Misguided transcriptional elongation causes mixed lineage leukemia. PLoS Biol. 2009;7:e1000249 pubmed publisher..In summary, we show aberrant transcriptional elongation as a novel mechanism for oncogenic transformation. ..
- Amente S, Gargano B, Napolitano G, Lania L, Majello B. Camptothecin releases P-TEFb from the inactive 7SK snRNP complex. Cell Cycle. 2009;8:1249-55 pubmed..The findings that CPT affects P-TEFb activity provide a direct evidence of the mechanism of this drug to inhibit transcription. ..
- Moiola C, De Luca P, Gardner K, Vazquez E, De Siervi A. Cyclin T1 overexpression induces malignant transformation and tumor growth. Cell Cycle. 2010;9:3119-26 pubmed publisher..All these data demonstrate for the first time the Cyclin T1 oncogenic function and suggest a role for this protein in controlling cell cycle probably via Rb/E2F1 pathway. ..
- Yang B, Yuan J, Gao X, Qin W, Liu F, Shao C, et al. [Expression of cell cycle molecules in human azoospermic testes]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2009;25:393-5 pubmed..The cell cycle molecules such as CDC10, CDC7L1, CDK9, CDC20 and CLK3 may play a role in the development and progression of azoospermia. ..
- Wagner N, Jehl Pietri C, Lopez P, Murdaca J, Giordano C, Schwartz C, et al. Peroxisome proliferator-activated receptor beta stimulation induces rapid cardiac growth and angiogenesis via direct activation of calcineurin. Cardiovasc Res. 2009;83:61-71 pubmed publisher..Our data suggest PPARbeta pharmacological activation as a novel approach to increase cardiac vascularization and cardiac muscle mass. ..
- O Brien S, Cao H, Nathans R, Ali A, Rana T. P-TEFb kinase complex phosphorylates histone H1 to regulate expression of cellular and HIV-1 genes. J Biol Chem. 2010;285:29713-20 pubmed publisher..We identify histone H1 as a novel P-TEFb substrate, and our results suggest new roles for P-TEFb in both cellular and HIV-1 transcription. ..
- Viladevall L, St Amour C, Rosebrock A, Schneider S, Zhang C, Allen J, et al. TFIIH and P-TEFb coordinate transcription with capping enzyme recruitment at specific genes in fission yeast. Mol Cell. 2009;33:738-51 pubmed publisher..In vitro, phosphorylation of the CTD by Mcs6 stimulates subsequent phosphorylation by Cdk9. We propose that TFIIH primes the CTD and promotes recruitment of P-TEFb/Pcm1, serving to couple elongation and capping of select pre-mRNAs. ..
- Mikula M, Hanusek K, Paziewska A, Dzwonek A, Rubel T, Bomsztyk K, et al. Halogenated imidazole derivatives block RNA polymerase II elongation along mitogen inducible genes. BMC Mol Biol. 2010;11:4 pubmed publisher..Our approach revealed that small molecules derived from halogenated imidazole compounds may decrease cell proliferation, in part, by inhibiting pathways that regulate transcription elongation. ..
- Dong C, Kwas C, Wu L. Transcriptional restriction of human immunodeficiency virus type 1 gene expression in undifferentiated primary monocytes. J Virol. 2009;83:3518-27 pubmed publisher..Our results provide new insights into HIV-1 infection and regulation in primary monocytes and viral pathogenesis. ..
- Khiati A, Chaloin O, Muller S, Tardieu M, Horellou P. Induction of monocyte chemoattractant protein-1 (MCP-1/CCL2) gene expression by human immunodeficiency virus-1 Tat in human astrocytes is CDK9 dependent. J Neurovirol. 2010;16:150-67 pubmed publisher..We have ascertained the direct implication of cdk9 in Tat-induced MCP-1 expression by performing ChIP assay. These results demonstrate that cdk9 is involved in Tat-induced HIV-1 LTR, MCP-1/CCL2 gene expression. ..
- Rechter S, Scott G, Eickhoff J, Zielke K, Auerochs S, Müller R, et al. Cyclin-dependent Kinases Phosphorylate the Cytomegalovirus RNA Export Protein pUL69 and Modulate Its Nuclear Localization and Activity. J Biol Chem. 2009;284:8605-13 pubmed publisher..Thus, our data underline the crucial importance of CDKs for HCMV replication, and indicate a direct impact of CDK9-cyclin T1 on the nuclear localization and activity of the viral regulator pUL69. ..
- Pirngruber J, Shchebet A, Johnsen S. Insights into the function of the human P-TEFb component CDK9 in the regulation of chromatin modifications and co-transcriptional mRNA processing. Cell Cycle. 2009;8:3636-42 pubmed
- Johnson L. The regulation of protein phosphorylation. Biochem Soc Trans. 2009;37:627-41 pubmed publisher..Finally, I consider recent advances on protein kinases as drug targets and describe some of our recent work with CDK9 (cyclin-dependent kinase 9)-cyclin T, a regulator of transcription. ..
- Pirngruber J, Shchebet A, Schreiber L, Shema E, Minsky N, Chapman R, et al. CDK9 directs H2B monoubiquitination and controls replication-dependent histone mRNA 3'-end processing. EMBO Rep. 2009;10:894-900 pubmed publisher..Thus, CDK9 acts to integrate phosphorylation during transcription with chromatin modifications to control co-transcriptional histone mRNA processing. ..
- Byth K, Thomas A, Hughes G, Forder C, McGregor A, Geh C, et al. AZD5438, a potent oral inhibitor of cyclin-dependent kinases 1, 2, and 9, leads to pharmacodynamic changes and potent antitumor effects in human tumor xenografts. Mol Cancer Ther. 2009;8:1856-66 pubmed publisher..These data indicate that broad cdk inhibition may provide an effective method to impair the dysregulated cell cycle that drives tumorigenesis and AZD5438 has the pharmacologic profile that provides an ideal probe to test this premise. ..
- Guo W, Wu S, Wang L, Wang R, Wei X, Liu J, et al. Interruption of RNA processing machinery by a small compound, 1-[(4-chlorophenyl)methyl]-1H-indole-3-carboxaldehyde (oncrasin-1). Mol Cancer Ther. 2009;8:441-8 pubmed publisher..Together, our results suggest that oncrasin-1 suppresses the function of RNA processing machinery and that PKCiota might be involved in the biological function of RNA processing complexes. ..
- Alarcon C, Zaromytidou A, Xi Q, Gao S, Yu J, Fujisawa S, et al. Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-beta pathways. Cell. 2009;139:757-69 pubmed publisher..Thus, nuclear CDK8/9 drive a cycle of Smad utilization and disposal that is an integral part of canonical BMP and TGF-beta pathways. ..
- Garriga J, Xie H, Obradovic Z, Grana X. Selective control of gene expression by CDK9 in human cells. J Cell Physiol. 2010;222:200-8 pubmed publisher..Our data suggests that the potent effects of FVP on transcription are likely to involve inhibition of CTD kinases in addition to CDK9. Our data also suggest complex and gene-specific modulation of gene expression by CDK9. ..
- Krystof V, Chamrad I, Jorda R, Kohoutek J. Pharmacological targeting of CDK9 in cardiac hypertrophy. Med Res Rev. 2010;30:646-66 pubmed publisher..CDK9 may therefore constitute a novel target for drugs against cardiac hypertrophy. ..
- Glover Cutter K, Larochelle S, Erickson B, Zhang C, Shokat K, Fisher R, et al. TFIIH-associated Cdk7 kinase functions in phosphorylation of C-terminal domain Ser7 residues, promoter-proximal pausing, and termination by RNA polymerase II. Mol Cell Biol. 2009;29:5455-64 pubmed publisher..Consistent with a new role for TFIIH at 3' ends, it was detected within genes and 3'-flanking regions, and Cdk7 inhibition delayed pausing and transcription termination. ..
- Tahirov T, Babayeva N, Varzavand K, Cooper J, Sedore S, Price D. Crystal structure of HIV-1 Tat complexed with human P-TEFb. Nature. 2010;465:747-51 pubmed publisher..Importantly, Tat induces significant conformational changes in P-TEFb. This finding lays a foundation for the design of compounds that would specifically inhibit the Tat.P-TEFb complex and block HIV replication. ..
- Kaichi S, Takaya T, Morimoto T, Sunagawa Y, Kawamura T, Ono K, et al. Cyclin-dependent kinase 9 forms a complex with GATA4 and is involved in the differentiation of mouse ES cells into cardiomyocytes. J Cell Physiol. 2011;226:248-54 pubmed publisher..5 mRNA levels in ES cells as well as GFP expression in Nkx2.5/GFP ES cells. These findings demonstrate that Cdk9 is involved in the differentiation of mouse ES cells into cardiomyocytes by interacting with GATA4. ..
- Kapasi A, Clark C, Tran K, Spector D. Recruitment of cdk9 to the immediate-early viral transcriptosomes during human cytomegalovirus infection requires efficient binding to cyclin T1, a threshold level of IE2 86, and active transcription. J Virol. 2009;83:5904-17 pubmed publisher..Exogenous expression of additional cdk9 mutants indicates that binding of Brd4 to the cdk9 complex is not required but that efficient binding to cyclin T1 is essential. ..