Cyclins that don't cycle--cyclin T/cyclin-dependent kinase-9 determines cardiac muscle cell size.

Motoaki Sano, Michael D. Schneider

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)99-104
Number of pages6
JournalCell cycle (Georgetown, Tex.)
Volume2
Issue number2
Publication statusPublished - 2003 Mar
Externally publishedYes

Fingerprint

Cyclin-Dependent Kinase 9
Cyclin T
Small Nuclear RNA
Cyclins
Cell Size
Cardiac Myocytes
Hypertrophy
Muscle
Phosphotransferases
Chemical activation
Cells
General Transcription Factors
Monomeric GTP-Binding Proteins
Cyclin-Dependent Kinases
RNA Polymerase II
Cell growth
Endothelin-1
Transcription
Machinery
Genes

ASJC Scopus subject areas

  • Cell Biology
  • Biochemistry
  • Molecular Biology

Cite this

Cyclins that don't cycle--cyclin T/cyclin-dependent kinase-9 determines cardiac muscle cell size. / Sano, Motoaki; Schneider, Michael D.

In: Cell cycle (Georgetown, Tex.), Vol. 2, No. 2, 03.2003, p. 99-104.

Research output: Contribution to journalArticle

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