A subset of
cyclin-dependent
protein kinases--Cdk7, Cdk8, and Cdk9--participates directly, in complex ways, with the fundamental machinery for gene transcription, as elements of
general transcription factors whose substrate is the C-terminal domain (CTD) of
RNA polymerase II. Here, we review recent data implicating the
CTD kinase Cdk9 as a critical determinant of
cardiac hypertrophy, in vitro and in vivo. Diverse trophic signals that increase cardiac mass all activated Cdk9 (work load, the
small G-protein Gaq, and the
calcium-dependent
phosphatase calcineurin in mouse myocardium;
endothelin-1, a hypertrophic agonist, in cultured cardiomyocytes). Little or no change occurred in levels of the
kinase or its activator,
cyclin T. Instead, in all four hypertrophic models, Cdk9 activation involves the dissociation of 7SK
small nuclear RNA (
snRNA), an endogenous inhibitor. In culture, dominant-negative Cdk9 blocked ET-1-induced
hypertrophy, whereas an anti-sense "knockdown" of 7SK
snRNA provoked spontaneous cell growth. In trans-
genie mice, concordant with these results, activation of Cdk9 activity via cardiac-specific overexpression of
cyclin Tl suffices to provoke
hypertrophy. Together, these findings implicate Cdk9 activity as a pivotal regulator of pathophysiological heart growth. Because
hypertrophy, in turn, is a cardinal risk factor for developing cardiac pump failure, these results support the logic of examining Cdk9 as a potential
drug target in
heart disease.