Activation of cardiac Cdk9 represses PGC-1 and confers a predisposition to heart failure

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, st...

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Bibliographic Details
Published in:The EMBO journal 2004-09, Vol.23 (17), p.3559-3569
Main Authors: Sano, Motoaki, Wang, Sam C, Shirai, Manabu, Scaglia, Fernando, Xie, Min, Sakai, Satoshi, Tanaka, Toru, Kulkarni, Prathit A, Barger, Philip M, Youker, Keith A, Taffet, George E, Hamamori, Yasuo, Michael, Lloyd H, Craigen, William J, Schneider, Michael D
Format: Article
Language:English
Subjects:
Animals
Apoptosis
cardiac
Cells, Cultured
Cyclin T
Cyclin-Dependent Kinase 9 - metabolism
cyclin-dependent kinase-9
Cyclins - metabolism
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Enzyme Activation
Gene Expression
heart failure
Heart Failure - etiology
Heart Failure - genetics
Heart Failure - metabolism
Humans
Mice
mitochondria
Myocardium - metabolism
Myocytes, Cardiac - metabolism
Myocytes, Cardiac - pathology
NF-E2-Related Factor 1
Nuclear Respiratory Factor 1
Nuclear Respiratory Factors
Promoter Regions, Genetic
Rats
RNA Polymerase II - metabolism
Trans-Activators - genetics
Trans-Activators - metabolism
Transcription Factors - genetics
Transcription Factors - metabolism
Transcription, Genetic
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Summary: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 αMHC‐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.
ISSN:0261-4189
1460-2075
DOI:10.1038/sj.emboj.7600351