Nature Medicine
8, 1310 - 1317 (2002)
Published online: 30 September 2002; Corrected online: 16 October 2002 | doi:10.1038/nm778
Activation and function of cyclin T−Cdk9 (positive transcription elongation factor-b) in cardiac muscle-cell hypertrophyMotoaki Sano1, 3, Maha Abdellatif6, Hidemasa Oh1, 3, Min Xie1, 3, Luigi Bagella7, Antonio Giordano7, Lloyd H. Michael2, 3, Francesco J. DeMayo4
& Michael D. Schneider1, 3, 4, 51
Center for Cardiovascular Development, Baylor College of Medicine, Texas, USA
2
DeBakey Heart Center, Baylor College of Medicine, Texas, USA
3
Department of Medicine, Baylor College of Medicine, Texas, USA
4
Departments of Molecular and Cellular Biology, Baylor College of Medicine, Texas, USA
5
Departments of Molecular Physiology and Biophysics, Baylor College of Medicine, Texas, USA
6
Cardiovascular Research Institute, Departments of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, Newark, New Jersey, USA
7
Sbarro Institute for Cancer Research and Molecular Medicine, College of Science and Technology, Temple University, Philadelphia, Pennsylvania, USA
Correspondence should be addressed to Michael D. Schneider michaels@bcm.tmc.eduHypertrophic growth is a risk factor for mortality in heart diseases. Mechanisms are lacking for this global increase in RNA and protein per cell, which underlies hypertrophy. Hypertrophic signals cause phosphorylation of the RNA polymerase II C-terminal domain, required for transcript elongation. RNA polymerase II kinases include cyclin-dependent kinases-7 (Cdk7) and Cdk9, components of two basal transcription factors. We report activation of Cdk7 and -9 in hypertrophy triggered by signaling proteins (G q, calcineurin) or chronic mechanical stress. Only Cdk9 was activated by acute load or, in culture, by endothelin. A preferential role for Cdk9 was shown in RNA polymerase II phosphorylation and growth induced by endothelin, using pharmacological and dominant-negative inhibitors. All four hypertrophic signals dissociated 7SK small nuclear RNA, an endogenous inhibitor, from cyclin T−Cdk9. Cdk9 was limiting for cardiac growth, shown by suppressing its inhibitor (7SK) in culture and preventing downregulation of its activator (cyclin T1) in mouse myocardium.
Note: In the AOP version of this article, the numbering of the author affiliations was incorrect. This has now been fixed, and the affiliations appear correctly online and in print.
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