TY - JOUR
T1 - CTIP2 is a negative regulator of P-TEFb
AU - Cherrier, Thomas
AU - Le Douce, Valentin
AU - Eilebrecht, Sebastian
AU - Riclet, Raphael
AU - Marban, Céline
AU - Dequiedt, Franck
AU - Goumon, Yannick
AU - Paillart, Jean Christophe
AU - Mericskay, Mathias
AU - Parlakian, Ara
AU - Bausero, Pedro
AU - Abbas, Wasim
AU - Herbein, Georges
AU - Kurdistani, Siavash K.
AU - Grana, Xavier
AU - Van Driessche, Benoit
AU - Schwartz, Christian
AU - Candolfi, Ermanno
AU - Benecke, Arndt G.
AU - Van Lint, Carine
AU - Rohr, Olivier
PY - 2013/7/30
Y1 - 2013/7/30
N2 - 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.
AB - 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.
KW - Animals
KW - Cardiac Myosins/genetics
KW - Cardiomegaly/genetics
KW - Cyclin-Dependent Kinase 9/genetics
KW - HEK293 Cells
KW - Humans
KW - Mice
KW - Myosin Heavy Chains/genetics
KW - Positive Transcriptional Elongation Factor B/genetics
KW - Promoter Regions, Genetic
KW - Protein Structure, Secondary
KW - RNA, Small Nuclear/genetics
KW - RNA-Binding Proteins/genetics
KW - Repressor Proteins/genetics
KW - Transcription Factors/genetics
KW - Tumor Suppressor Proteins/genetics
UR - http://www.scopus.com/inward/record.url?scp=84881094941&partnerID=8YFLogxK
U2 - 10.1073/pnas.1220136110
DO - 10.1073/pnas.1220136110
M3 - Article
C2 - 23852730
SN - 0027-8424
VL - 110
SP - 12655
EP - 12660
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 31
ER -