CTIP2 is a negative regulator of P-TEFb

Thomas Cherrier (1, 2) , Valentin Le Douce (1) , Sebastian Eilebrecht (3) , Raphael Riclet (1) , Celine Marban (1, 4) , Franck Dequiedt (2) , Yannick Goumon (5) , Jean-Christophe Paillart (6) , Mathias Mericskay (7) , Ara Parlakian (7) , Pedro Bausero (7) , Wasim Abbas (8) , Georges Herbein (8) , Siavash K. Kurdistani (9) , Xavier Grana (10) , Benoit van Driessche (11) , Christian Schwartz (1) , Ermanno Candolfi (1) , Arndt G. Benecke (3, 12) , Carine van Lint (11) , Olivier Rohr (1, 13)

1 IPPTS - Institut de Parasitologie et de Pathologie Tropicale
2 Université de Liège
3 IMRB - Institut Mondor de Recherche Biomédicale
4 UC - University of California
5 INCI - Institut des Neurosciences Cellulaires et Intégratives
6 ARN - Architecture et Réactivité de l'ARN
7 Vieillissement, stress, inflammation
8 IBCT (ex IFR133) - Ingénierie et biologie cellulaire et tissulaire
9 UCLA - University of California [Los Angeles]
10 Temple University [Philadelphia]
11 ULB/IBMM - Institut de Biologie et de Médecine Moléculaires [Gosselies]
12 IHES - Institut des Hautes Études Scientifiques
13 IUF - Institut universitaire de France

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 beta-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.

Domaines: Neurosciences [q-bio.NC]

Thomas Cherrier, Valentin Le Douce, Sebastian Eilebrecht, Raphael Riclet, Celine Marban, et al.. CTIP2 is a negative regulator of P-TEFb. Proceedings of the National Academy of Sciences of the United States of America, 2013, 110 (31), pp.12655-12660. ⟨10.1073/pnas.1220136110⟩. ⟨hal-01544149⟩