| Structural highlights
Disease
CDK9_HUMAN Note=Chronic activation of CDK9 causes cardiac myocyte enlargement leading to cardiac hypertrophy, and confers predisposition to heart failure.
Function
CDK9_HUMAN Protein kinase involved in the regulation of transcription. Member of the cyclin-dependent kinase pair (CDK9/cyclin-T) complex, also called positive transcription elongation factor b (P-TEFb), which facilitates the transition from abortive to productive elongation by phosphorylating the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAP II) POLR2A, SUPT5H and RDBP. This complex is inactive when in the 7SK snRNP complex form. Phosphorylates EP300, MYOD1, RPB1/POLR2A and AR, and the negative elongation factors DSIF and NELF. Regulates cytokine inducible transcription networks by facilitating promoter recognition of target transcription factors (e.g. TNF-inducible RELA/p65 activation and IL-6-inducible STAT3 signaling). Promotes RNA synthesis in genetic programs for cell growth, differentiation and viral pathogenesis. P-TEFb is also involved in cotranscriptional histone modification, mRNA processing and mRNA export. Modulates a complex network of chromatin modifications including histone H2B monoubiquitination (H2Bub1), H3 lysine 4 trimethylation (H3K4me3) and H3K36me3; integrates phosphorylation during transcription with chromatin modifications to control co-transcriptional histone mRNA processing. The CDK9/cyclin-K complex has also a kinase activity towards CTD of RNAP II and can substitute for CDK9/cyclin-T P-TEFb in vitro. Replication stress response protein; the CDK9/cyclin-K complex is required for genome integrity maintenance, by promoting cell cycle recovery from replication arrest and limiting single-stranded DNA amount in response to replication stress, thus reducing the breakdown of stalled replication forks and avoiding DNA damage. In addition, probable function in DNA repair of isoform 2 via interaction with KU70/XRCC6. Promotes cardiac myocyte enlargement. RPB1/POLR2A phosphorylation on 'Ser-2' in CTD activates transcription. AR phosphorylation modulates AR transcription factor promoter selectivity and cell growth. DSIF and NELF phosphorylation promotes transcription by inhibiting their negative effect. The phosphorylation of MYOD1 enhances its transcriptional activity and thus promotes muscle differentiation.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22]
Publication Abstract from PubMed
CDK9 is the kinase of positive transcription elongation factor b and facilitates the transition of paused RNA polymerase II to processive transcription elongation. CDK9 is a validated target for the treatment of cancer, cardiac hypertrophy, and human immunodeficiency virus. Here we analyze different CDK9/cyclin T variants to identify a form of the complex amenable to use in inhibitor design. To demonstrate the utility of this system, we have determined the crystal structures of CDK9/cyclin T and CDK2/cyclin A bound to the CDK9-specific inhibitor CAN508. Comparison of the structures reveals CDK9-specific conformational changes and identifies a CDK9-specific hydrophobic pocket, adjacent to the alphaC-helix. By comparison with a previously published structure of CDK9/cyclin T/human immunodeficiency virus TAT we find that the CDK9 alphaC-helix has a degree of conformational variability that has the potential to be exploited for inhibitor design.
The CDK9 C-helix Exhibits Conformational Plasticity That May Explain the Selectivity of CAN508.,Baumli S, Hole AJ, Noble ME, Endicott JA ACS Chem Biol. 2012 Feb 10. PMID:22292676[23]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Wada T, Takagi T, Yamaguchi Y, Watanabe D, Handa H. Evidence that P-TEFb alleviates the negative effect of DSIF on RNA polymerase II-dependent transcription in vitro. EMBO J. 1998 Dec 15;17(24):7395-403. PMID:9857195 doi:10.1093/emboj/17.24.7395
- ↑ Parada CA, Roeder RG. A novel RNA polymerase II-containing complex potentiates Tat-enhanced HIV-1 transcription. EMBO J. 1999 Jul 1;18(13):3688-701. PMID:10393184 doi:10.1093/emboj/18.13.3688
- ↑ Fu TJ, Peng J, Lee G, Price DH, Flores O. Cyclin K functions as a CDK9 regulatory subunit and participates in RNA polymerase II transcription. J Biol Chem. 1999 Dec 3;274(49):34527-30. PMID:10574912
- ↑ Wada T, Orphanides G, Hasegawa J, Kim DK, Shima D, Yamaguchi Y, Fukuda A, Hisatake K, Oh S, Reinberg D, Handa H. FACT relieves DSIF/NELF-mediated inhibition of transcriptional elongation and reveals functional differences between P-TEFb and TFIIH. Mol Cell. 2000 Jun;5(6):1067-72. PMID:10912001
- ↑ Ivanov D, Kwak YT, Guo J, Gaynor RB. Domains in the SPT5 protein that modulate its transcriptional regulatory properties. Mol Cell Biol. 2000 May;20(9):2970-83. PMID:10757782
- ↑ Kim JB, Sharp PA. Positive transcription elongation factor B phosphorylates hSPT5 and RNA polymerase II carboxyl-terminal domain independently of cyclin-dependent kinase-activating kinase. J Biol Chem. 2001 Apr 13;276(15):12317-23. Epub 2001 Jan 5. PMID:11145967 doi:10.1074/jbc.M010908200
- ↑ Ping YH, Rana TM. DSIF and NELF interact with RNA polymerase II elongation complex and HIV-1 Tat stimulates P-TEFb-mediated phosphorylation of RNA polymerase II and DSIF during transcription elongation. J Biol Chem. 2001 Apr 20;276(16):12951-8. Epub 2000 Dec 8. PMID:11112772 doi:10.1074/jbc.M006130200
- ↑ Lavoie SB, Albert AL, Handa H, Vincent M, Bensaude O. The peptidyl-prolyl isomerase Pin1 interacts with hSpt5 phosphorylated by Cdk9. J Mol Biol. 2001 Sep 28;312(4):675-85. PMID:11575923 doi:10.1006/jmbi.2001.4991
- ↑ Lin X, Taube R, Fujinaga K, Peterlin BM. P-TEFb containing cyclin K and Cdk9 can activate transcription via RNA. J Biol Chem. 2002 May 10;277(19):16873-8. Epub 2002 Mar 7. PMID:11884399 doi:10.1074/jbc.M200117200
- ↑ Bourgeois CF, Kim YK, Churcher MJ, West MJ, Karn J. Spt5 cooperates with human immunodeficiency virus type 1 Tat by preventing premature RNA release at terminator sequences. Mol Cell Biol. 2002 Feb;22(4):1079-93. PMID:11809800
- ↑ Simone C, Stiegler P, Bagella L, Pucci B, Bellan C, De Falco G, De Luca A, Guanti G, Puri PL, Giordano A. Activation of MyoD-dependent transcription by cdk9/cyclin T2. Oncogene. 2002 Jun 13;21(26):4137-48. PMID:12037670 doi:10.1038/sj.onc.1205493
- ↑ Zhou M, Deng L, Lacoste V, Park HU, Pumfery A, Kashanchi F, Brady JN, Kumar A. Coordination of transcription factor phosphorylation and histone methylation by the P-TEFb kinase during human immunodeficiency virus type 1 transcription. J Virol. 2004 Dec;78(24):13522-33. PMID:15564463 doi:78/24/13522
- ↑ Fujinaga K, Irwin D, Huang Y, Taube R, Kurosu T, Peterlin BM. Dynamics of human immunodeficiency virus transcription: P-TEFb phosphorylates RD and dissociates negative effectors from the transactivation response element. Mol Cell Biol. 2004 Jan;24(2):787-95. PMID:14701750
- ↑ Hou T, Ray S, Brasier AR. The functional role of an interleukin 6-inducible CDK9.STAT3 complex in human gamma-fibrinogen gene expression. J Biol Chem. 2007 Dec 21;282(51):37091-102. Epub 2007 Oct 23. PMID:17956865 doi:10.1074/jbc.M706458200
- ↑ Nowak DE, Tian B, Jamaluddin M, Boldogh I, Vergara LA, Choudhary S, Brasier AR. RelA Ser276 phosphorylation is required for activation of a subset of NF-kappaB-dependent genes by recruiting cyclin-dependent kinase 9/cyclin T1 complexes. Mol Cell Biol. 2008 Jun;28(11):3623-38. doi: 10.1128/MCB.01152-07. Epub 2008 Mar , 24. PMID:18362169 doi:10.1128/MCB.01152-07
- ↑ Pirngruber J, Shchebet A, Johnsen SA. 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 Nov 15;8(22):3636-42. Epub 2009 Nov 24. PMID:19844166
- ↑ Pirngruber J, Shchebet A, Schreiber L, Shema E, Minsky N, Chapman RD, Eick D, Aylon Y, Oren M, Johnsen SA. CDK9 directs H2B monoubiquitination and controls replication-dependent histone mRNA 3'-end processing. EMBO Rep. 2009 Aug;10(8):894-900. doi: 10.1038/embor.2009.108. Epub 2009 Jul 3. PMID:19575011 doi:10.1038/embor.2009.108
- ↑ Liu H, Herrmann CH, Chiang K, Sung TL, Moon SH, Donehower LA, Rice AP. 55K isoform of CDK9 associates with Ku70 and is involved in DNA repair. Biochem Biophys Res Commun. 2010 Jun 25;397(2):245-50. doi:, 10.1016/j.bbrc.2010.05.092. Epub 2010 May 20. PMID:20493174 doi:10.1016/j.bbrc.2010.05.092
- ↑ Yu DS, Zhao R, Hsu EL, Cayer J, Ye F, Guo Y, Shyr Y, Cortez D. Cyclin-dependent kinase 9-cyclin K functions in the replication stress response. EMBO Rep. 2010 Nov;11(11):876-82. doi: 10.1038/embor.2010.153. Epub 2010 Oct 8. PMID:20930849 doi:10.1038/embor.2010.153
- ↑ Sunagawa Y, Morimoto T, Takaya T, Kaichi S, Wada H, Kawamura T, Fujita M, Shimatsu A, Kita T, Hasegawa K. Cyclin-dependent kinase-9 is a component of the p300/GATA4 complex required for phenylephrine-induced hypertrophy in cardiomyocytes. J Biol Chem. 2010 Mar 26;285(13):9556-68. doi: 10.1074/jbc.M109.070458. Epub 2010, Jan 17. PMID:20081228 doi:10.1074/jbc.M109.070458
- ↑ Gordon V, Bhadel S, Wunderlich W, Zhang J, Ficarro SB, Mollah SA, Shabanowitz J, Hunt DF, Xenarios I, Hahn WC, Conaway M, Carey MF, Gioeli D. CDK9 regulates AR promoter selectivity and cell growth through serine 81 phosphorylation. Mol Endocrinol. 2010 Dec;24(12):2267-80. doi: 10.1210/me.2010-0238. Epub 2010 Oct, 27. PMID:20980437 doi:10.1210/me.2010-0238
- ↑ Cojocaru M, Bouchard A, Cloutier P, Cooper JJ, Varzavand K, Price DH, Coulombe B. Transcription factor IIS cooperates with the E3 ligase UBR5 to ubiquitinate the CDK9 subunit of the positive transcription elongation factor B. J Biol Chem. 2011 Feb 18;286(7):5012-22. doi: 10.1074/jbc.M110.176628. Epub 2010 , Dec 2. PMID:21127351 doi:10.1074/jbc.M110.176628
- ↑ Baumli S, Hole AJ, Noble ME, Endicott JA. The CDK9 C-helix Exhibits Conformational Plasticity That May Explain the Selectivity of CAN508. ACS Chem Biol. 2012 Feb 10. PMID:22292676 doi:10.1021/cb2004516
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