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Comparative Study
. 2004 Oct 29;95(9):867-76.
doi: 10.1161/01.RES.0000146675.88354.04.

Cyclin-dependent kinase-9: an RNAPII kinase at the nexus of cardiac growth and death cascades

Motoaki Sano  1 , Michael D Schneider
Affiliations
Comparative Study

Cyclin-dependent kinase-9: an RNAPII kinase at the nexus of cardiac growth and death cascades

Motoaki Sano et al. Circ Res. .

Abstract

Over the past decade and a half, the paradigm has emerged of cardiac hypertrophy and ensuing heart failure as fundamentally a problem in signal transduction, impinging on the altered expression or function of gene-specific transcription factors and their partners, which then execute the hypertrophic phenotype. Strikingly, RNA polymerase II (RNAPII) is itself a substrate for two protein kinases-the cyclin-dependent kinases Cdk7 and Cdk9--that are activated by hypertrophic cues. Phosphorylation of RNAPII in the carboxyl terminal domain (CTD) of its largest subunit controls a number of critical steps subsequent to transcription initiation, among them enabling RNAPII to overcome its stalling in the promoter-proximal region and to engage in efficient transcription elongation. Here, we summarize our current understanding of the RNAPII-directed protein kinases in cardiac hypertrophy. Cdk9 activation is essential in tissue culture for myocyte enlargement and sufficient in transgenic mice for hypertrophy to occur and yet is unrelated to the "fetal" gene program that is typical of pathophysiological heart growth. Although this trophic effect of Cdk9 appears benign superficially, pathophysiological levels of Cdk9 activity render myocardium remarkably susceptible to apoptotic stress. Cdk9 interacts adversely with Gq-dependent pathways for hypertrophy, impairing the expression of numerous genes for mitochondrial proteins, and, in particular, suppressing master regulators of mitochondrial biogenesis and function, perioxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1), and nuclear respiratory factor-1 (NRF-1). Given the dual transcriptional roles of Cdk9 in hypertrophic growth and mitochondrial dysfunction, we suggest the potential usefulness of Cdk9 as a target in heart failure drug discovery.

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