title: CTIP2 is a negative regulator of P-TEFb.
abstract: The positive transcription elongation factor b (P-TEFb) is involved in physiological and pathological events including inflammation, cancer, AIDS, and cardiac hypertrophy. The balance between its active and inactive form is tightly controlled to ensure cellular integrity. We report that the transcriptional repressor CTIP2 is a major modulator of P-TEFb activity. CTIP2 copurifies and interacts with an inactive P-TEFb complex containing the 7SK snRNA and HEXIM1. CTIP2 associates directly with HEXIM1 and, via the loop 2 of the 7SK snRNA, with P-TEFb. In this nucleoprotein complex, CTIP2 significantly represses the Cdk9 kinase activity of P-TEFb. Accordingly, we show that CTIP2 inhibits large sets of P-TEFb- and 7SK snRNA-sensitive genes. In hearts of hypertrophic cardiomyopathic mice, CTIP2 controls P-TEFb-sensitive pathways involved in the establishment of this pathology. Overexpression of the β-myosin heavy chain protein contributes to the pathological cardiac wall thickening. The inactive P-TEFb complex associates with CTIP2 at the MYH7 gene promoter to repress its activity. Taken together, our results strongly suggest that CTIP2 controls P-TEFb function in physiological and pathological conditions.
authors.affiliation: Institut de Parasitologie et de Pathologie Tropicale, Fédération de Médecine Translationnelle, University of Strasbourg, 67000 Strasbourg, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Cherrier
authors.forename: Valentin
authors.initials: V
authors.lastname: Le Douce
authors.forename: Sebastian
authors.initials: S
authors.lastname: Eilebrecht
authors.forename: Raphael
authors.initials: R
authors.lastname: Riclet
authors.forename: Céline
authors.initials: C
authors.lastname: Marban
authors.forename: Franck
authors.initials: F
authors.lastname: Dequiedt
authors.forename: Yannick
authors.initials: Y
authors.lastname: Goumon
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Paillart
authors.forename: Mathias
authors.initials: M
authors.lastname: Mericskay
authors.forename: Ara
authors.initials: A
authors.lastname: Parlakian
authors.forename: Pedro
authors.initials: P
authors.lastname: Bausero
authors.forename: Wasim
authors.initials: W
authors.lastname: Abbas
authors.forename: Georges
authors.initials: G
authors.lastname: Herbein
authors.forename: Siavash K
authors.initials: SK
authors.lastname: Kurdistani
authors.forename: Xavier
authors.initials: X
authors.lastname: Grana
authors.forename: Benoit
authors.initials: B
authors.lastname: Van Driessche
authors.forename: Christian
authors.initials: C
authors.lastname: Schwartz
authors.forename: Ermanno
authors.initials: E
authors.lastname: Candolfi
authors.forename: Arndt G
authors.initials: AG
authors.lastname: Benecke
authors.forename: Carine
authors.initials: C
authors.lastname: Van Lint
authors.forename: Olivier
authors.initials: O
authors.lastname: Rohr
mesh_terms: D000818:Animals; D024722:Cardiac Myosins / Q000235:genetics / Q000378:metabolism; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D042863:Cyclin-Dependent Kinase 9 / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D042925:Positive Transcriptional Elongation Factor B / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D017433:Protein Structure, Secondary; D012342:RNA, Small Nuclear / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C479740:BCL11B protein, human; C511143:Bcl11b protein, mouse; C476123:HEXIM1 protein, human; C118642:Hexim1 protein, mouse; C501641:MYH7 protein, human; C551613:Myh7 protein, mouse; D012342:RNA, Small Nuclear; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D042925:Positive Transcriptional Elongation Factor B; C467969:CDK9 protein, human; C467972:Cdk9 protein, mouse; D042863:Cyclin-Dependent Kinase 9; D024722:Cardiac Myosins; D018995:Myosin Heavy Chains