title: Two-pronged binding with bromodomain-containing protein 4 liberates positive transcription elongation factor b from inactive ribonucleoprotein complexes.
abstract: The positive transcription elongation factor b (P-TEFb) exists in two forms in cells as follows: an inactive form where the core components cyclin T1 and CDK9 are incorporated in the 7SK small nuclear ribonucleoprotein complex containing the inhibitory molecule HEXIM1, and an active form, part of which associates with the bromodomain-containing protein BRD4. Here, we define a novel interaction between P-TEFb and BRD4 involving tri-acetylated cyclin T1 (acK380, acK386, and acK309) and the second bromodomain in BRD4. This interaction is observed with the short splice variant of BRD4 (amino acids 1-722) lacking a previously defined C-terminal P-TEFb-interacting domain (PID). Notably, P-TEFb complexes associated with short BRD4 contain HEXIM1 and 7SK snRNA, implicating the PID in the liberation of P-TEFb from the 7SK small nuclear ribonucleoprotein complex (7SK snPNP). Overexpression of the PID alone in cells dissociates HEXIM1 and 7SK snRNA from P-TEFb, but it is not sufficient to activate P-TEFb-dependent transcription of the HIV LTR. Our data support a model where two BRD4 domains, the second bromodomain and the PID, bind P-TEFb and are required for full transcriptional activation of P-TEFb response genes.
authors.affiliation: Gladstone Institute of Virology and Immunology, University of California, San Francisco, California 94158, USA.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schröder
authors.forename: Sungyoo
authors.initials: S
authors.lastname: Cho
authors.forename: Lei
authors.initials: L
authors.lastname: Zeng
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Katrin
authors.initials: K
authors.lastname: Kaehlcke
authors.forename: Lily
authors.initials: L
authors.lastname: Mak
authors.forename: Joann
authors.initials: J
authors.lastname: Lau
authors.forename: Dwayne
authors.initials: D
authors.lastname: Bisgrove
authors.forename: Martina
authors.initials: M
authors.lastname: Schnölzer
authors.forename: Eric
authors.initials: E
authors.lastname: Verdin
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Zhou
authors.forename: Melanie
authors.initials: M
authors.lastname: Ott
mesh_terms: D018797:Cell Cycle Proteins; D056906:Cyclin T / Q000235:genetics / Q000378:metabolism; D042863:Cyclin-Dependent Kinase 9 / Q000235:genetics / Q000378:metabolism; D016325:HIV Long Terminal Repeat / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D042925:Positive Transcriptional Elongation Factor B / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D012261:Ribonucleoproteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology*; D000092468:Bromodomain Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D056906:Cyclin T; D042863:Cyclin-Dependent Kinase 9; D009687:Nuclear Proteins; D042925:Positive Transcriptional Elongation Factor B; D016601:RNA-Binding Proteins; D012261:Ribonucleoproteins; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C503684:CCNT1 protein, human; C476123:HEXIM1 protein, human; C467969:CDK9 protein, human
references.citation: Mol Cell Biol. 2006 Oct;26(19):7068-76
references.pmid: 16980611
references.citation: FEBS Lett. 2008 Dec 10;582(29):4053-8
references.pmid: 18996376
references.citation: Cell Cycle. 2010 May;9(9):1697-705
references.pmid: 20436276
references.citation: Genes Dev. 2006 Sep 1;20(17):2383-96
references.pmid: 16921027
references.citation: PLoS Pathog. 2007 Oct 12;3(10):1459-69
references.pmid: 17937499
references.citation: PLoS One. 2010 Aug 23;5(8):e12335
references.pmid: 20808803
references.citation: Mol Cell. 2006 Aug 4;23(3):297-305
references.pmid: 16885020
references.citation: Proc Natl Acad Sci U S A. 2007 Sep 4;104(36):14312-7
references.pmid: 17724342
references.citation: Nature. 1999 Jun 3;399(6735):491-6
references.pmid: 10365964
references.citation: Nat Rev Mol Cell Biol. 2006 Aug;7(8):557-67
references.pmid: 16936696
references.citation: Mol Cell. 2006 Dec 28;24(6):877-89
references.pmid: 17189190
references.citation: J Virol. 1997 Aug;71(8):6113-27
references.pmid: 9223506
references.citation: Nature. 2000 Jan 6;403(6765):41-5
references.pmid: 10638745
references.citation: EMBO J. 2004 Jul 7;23(13):2608-19
references.pmid: 15201869
references.citation: Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3752-7
references.pmid: 20133580
references.citation: Mol Cell. 2005 Aug 19;19(4):535-45
references.pmid: 16109377
references.citation: EMBO J. 2009 May 20;28(10):1407-17
references.pmid: 19387490
references.citation: Science. 2000 May 26;288(5470):1422-5
references.pmid: 10827952
references.citation: Mol Cell Biol. 2002 Jun;22(11):3794-802
references.pmid: 11997514
references.citation: EMBO J. 2010 Sep 1;29(17):2943-52
references.pmid: 20676058
references.citation: Mol Cell. 2010 May 14;38(3):428-38
references.pmid: 20471948
references.citation: Curr Opin Genet Dev. 2008 Apr;18(2):130-6
references.pmid: 18282700
references.citation: Annu Rev Biochem. 2000;69:729-49
references.pmid: 10966474
references.citation: Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8538-43
references.pmid: 9671713
references.citation: Genes Dev. 2008 May 15;22(10):1356-68
references.pmid: 18483222
references.citation: Mol Cell. 2005 Aug 19;19(4):523-34
references.pmid: 16109376
references.citation: Front Biosci. 2001 Aug 01;6:D1008-18
references.pmid: 11487468
references.citation: J Biol Chem. 2008 Nov 28;283(48):33578-84
references.pmid: 18829461
references.citation: J Biol Chem. 2007 May 4;282(18):13141-5
references.pmid: 17329240
references.citation: Cancer Res. 2003 Jan 15;63(2):304-7
references.pmid: 12543779
references.citation: J Biol Chem. 2009 Dec 25;284(52):36547-36556
references.pmid: 19828451
references.citation: J Biol Chem. 2007 Feb 9;282(6):4193-201
references.pmid: 17148447
references.citation: Proc Natl Acad Sci U S A. 2007 Aug 21;104(34):13690-5
references.pmid: 17690245
references.citation: Cell. 2009 Sep 18;138(6):1122-36
references.pmid: 19766566
references.citation: Curr Biol. 1999 Dec 16-30;9(24):1489-92
references.pmid: 10607594
references.citation: Mol Cell. 2010 May 14;38(3):439-51
references.pmid: 20471949
references.citation: Mol Cell. 2003 Oct;12(4):971-82
references.pmid: 14580347
references.citation: Microbiol Mol Biol Rev. 2006 Sep;70(3):646-59
references.pmid: 16959964
references.citation: Proc Natl Acad Sci U S A. 2003 Jul 22;100(15):8758-63
references.pmid: 12840145
references.citation: Nature. 2009 Oct 1;461(7264):664-8
references.pmid: 19794495
references.citation: Structure. 2008 Apr;16(4):643-52
references.pmid: 18400184