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.
journal_name
Proc Natl Acad Sci U S Aauthors
Cherrier T,Le Douce V,Eilebrecht S,Riclet R,Marban C,Dequiedt F,Goumon Y,Paillart JC,Mericskay M,Parlakian A,Bausero P,Abbas W,Herbein G,Kurdistani SK,Grana X,Van Driessche B,Schwartz C,Candolfi E,Benecke AG,Van Lindoi
10.1073/pnas.1220136110subject
Has Abstractpub_date
2013-07-30 00:00:00pages
12655-60issue
31eissn
0027-8424issn
1091-6490pii
1220136110journal_volume
110pub_type
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