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Proc Natl Acad Sci U S A. 2013 Jul 30;110(31):12655-60. doi: 10.1073/pnas.1220136110. Epub 2013 Jul 12.

CTIP2 is a negative regulator of P-TEFb.

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  • 1Institut de Parasitologie et de Pathologie Tropicale, Fédération de Médecine Translationnelle, University of Strasbourg, 67000 Strasbourg, France.

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.

PMID:
23852730
PMCID:
PMC3732990
DOI:
10.1073/pnas.1220136110
[PubMed - indexed for MEDLINE]
Free PMC Article
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