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| Subject Categories: Differentiation & Death | Molecular Biology of Disease |
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| The EMBO Journal
(2004) 23, 3559–3569, doi:10.1038/sj.emboj.7600351 Published online 5 August 2004 |
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| Activation of cardiac Cdk9 represses PGC-1 and confers a predisposition to heart failure |
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| Motoaki Sano1, 2, Sam C Wang1, 2, Manabu Shirai1, 3, Fernando Scaglia4, Min Xie1, 2, Satoshi Sakai1, 2, Toru Tanaka1, 2, Prathit A Kulkarni1, 2, Philip M Barger2, 5, Keith A Youker6, 7, George E Taffet2, 6, Yasuo Hamamori1, 2, 3, Lloyd H Michael2, 6, William J Craigen4 and Michael D Schneider1, 2, 3, 8 |
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1 Center for Cardiovascular Development, Baylor College of Medicine, Houston, TX, USA 2 Department of Medicine, Baylor College of Medicine, Houston, TX, USA 3 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA 4 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA 5 Winters Center for Heart Failure Research, Baylor College of Medicine, Houston, TX, USA 6 The Methodist Hospital-DeBakey Heart Center, Baylor College of Medicine, Houston, TX, USA 7 Department of Surgery, Baylor College of Medicine, Houston, TX, USA 8 Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA To whom correspondence should be addressed Michael D Schneider, Center for Cardiovascular Development, Baylor College of Medicine, One Baylor Plaza, Room 506D, Houston, TX 77030, USA. Tel.: +1 713 798 6683; Fax: +1 713 798 7437; E-mail: michaels@bcm.tmc.edu Received 7 October 2003; Revised 8 July 2004; Published online 5 August 2004. |
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| Abstract |
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Hypertrophy allows the heart to adapt to workload but culminates in later pump failure; how it is achieved remains uncertain. Previously, we showed that hypertrophy is accompanied by activation of cyclin T/Cdk9, which phosphorylates the C-terminal domain of the large subunit of RNA polymerase II, stimulating transcription elongation and pre-mRNA processing; Cdk9 activity was required for hypertrophy in culture, whereas heart-specific activation of Cdk9 by cyclin T1 provoked hypertrophy in mice. Here, we report that  MHC-cyclin T1 mice appear normal at baseline yet suffer fulminant apoptotic cardiomyopathy when challenged by mechanical stress or signaling by the G-protein Gq. At pathophysiological levels, Cdk9 activity suppresses many genes for mitochondrial proteins including master regulators of mitochondrial function (peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1), nuclear respiratory factor-1). In culture, cyclin T1/Cdk9 suppresses PGC-1, decreases mitochondrial membrane potential, and sensitizes cardiomyocytes to apoptosis, effects rescued by exogenous PGC-1. Cyclin T1/Cdk9 inhibits PGC-1 promoter activity and preinitiation complex assembly. Thus, chronic activation of Cdk9 causes not only cardiomyocyte enlargement but also defective mitochondrial function, via diminished PGC-1 transcription, and a resulting susceptibility to apoptotic cardiomyopathy. |
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| Keywords: cardiac, cyclin-dependent kinase-9, cyclin T, heart failure, mitochondria |
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Top of page MORE ARTICLES LIKE THISThese links to content published by NPG are automatically generated RESEARCHNature Medicine Article (01 Nov 2002) Nature Medicine Article (01 Jul 2002) Nature Medicine Article (01 Jan 2003) The MEK1?ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice The EMBO Journal Article (01 Dec 2000) |
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