Cyclins that don't cycle--cyclin T/cyclin-dependent kinase-9 determines cardiac muscle cell size.
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.
Sano
Motoaki
M
Center for Cardiovascular Development, Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
Schneider
Michael D
MD
D000818:Animals; D006332:Cardiomegaly / Q000209:etiology*; D048429:Cell Size; D056906:Cyclin T; D042863:Cyclin-Dependent Kinase 9 / Q000378:metabolism / Q000502:physiology*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000502:physiology*; D006801:Humans; D051379:Mice; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000473:pathology; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism; D012319:RNA Polymerase II / Q000378:metabolism; D015398:Signal Transduction
C503684:CCNT1 protein, human; C503685:Ccnt1 protein, mouse; D056906:Cyclin T; D016213:Cyclins; D042925:Positive Transcriptional Elongation Factor B; D042863:Cyclin-Dependent Kinase 9; D018844:Cyclin-Dependent Kinases; D012319:RNA Polymerase II