CTIP2 is a negative regulator of P-TEFb.
Fiche publication
Date publication
juillet 2013
Journal
Proceedings of the National Academy of Sciences of the United States of America
Auteurs
Membres identifiés du Cancéropôle Est :
Pr HERBEIN Georges, Dr GOUMON Yannick, Pr ROHR Olivier
Tous les auteurs :
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 Lint C, Rohr O
Lien Pubmed
Résumé
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.
Mots clés
Animals, Cardiac Myosins, genetics, Cardiomegaly, genetics, Cyclin-Dependent Kinase 9, genetics, HEK293 Cells, Humans, Mice, Myosin Heavy Chains, genetics, Positive Transcriptional Elongation Factor B, genetics, Promoter Regions, Genetic, Protein Structure, Secondary, RNA, Small Nuclear, genetics, RNA-Binding Proteins, genetics, Repressor Proteins, genetics, Transcription Factors, genetics, Tumor Suppressor Proteins, genetics
Référence
Proc. Natl. Acad. Sci. U.S.A.. 2013 Jul;110(31):12655-60