期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 110, 期 31, 页码 12655-12660出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1220136110
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资金
- Agence Nationale de Recherches sur le SIDA et les Hepatites Virales (ANRS)
- Centre National de la Recherche Scientifique (CNRS, France)
- Agence Nationale de Recherches sur le SIDA et les hepatites virale (ANRS, France)
- Sidaction
- Institut Universitaire de France (IUF)
- Belgian Fund for Scientific Reseach (FRS-FNRS, Belgium)
- Televie Program of the FRS-FNRS
- Walloon Region (Excellence Program 'Cibles')
- Walloon Region [WALEO 021/5110]
- European AIDS treatment network (NEAT) integration grant
- Internationale Brachet Stiftung
- Fondation Roi Baudouin
- University of Franche-Comte
- National Institute of Mental Health [R21 MH083585]
- Pennsylvania Department of Health
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.
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