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(Circulation Research. 2008;102:1222.)
© 2008 American Heart Association, Inc.

Cellular Biology

A Cyclin D2–Rb Pathway Regulates Cardiac Myocyte Size and RNA Polymerase III After Biomechanical Stress in Adult Myocardium

Ekaterini Angelis, Alejandro Garcia, Shing S. Chan, Katja Schenke-Layland, Shuxen Ren, Sarah J. Goodfellow, Maria C. Jordan, Kenneth P. Roos, Robert J. White, W. Robb MacLellan

From the Cardiovascular Research Laboratory, Departments of Medicine (E.A., A.G., S.S.C., K.S.-L., W.R.M.), Physiology (M.C.J., K.P.R., W.R.M.), and Anesthesiology (S.R.), David Geffen School of Medicine at the University of California, Los Angeles; and Institute of Biomedical and Life Sciences (S.J.G., R.J.W.), University of Glasgow, United Kingdom.

Correspondence to W. Robb MacLellan, The Cardiovascular Research Laboratory, David Geffen School of Medicine at UCLA, 675 C E Young Dr, MRL 3-645, Los Angeles, CA 90095-1760. E-mail rmaclellan{at}mednet.ucla.edu

Normally, cell cycle progression is tightly coupled to the accumulation of cell mass; however, the mechanisms whereby proliferation and cell growth are linked are poorly understood. We have identified cyclin (Cyc)D2, a G₁ cyclin implicated in mediating S phase entry, as a potential regulator of hypertrophic growth in adult post mitotic myocardium. To examine the role of CycD2 and its downstream targets, we subjected CycD2-null mice to mechanical stress. Hypertrophic growth in response to transverse aortic constriction was attenuated in CycD2-null compared with wild-type mice. Blocking the increase in CycD2 in response to hypertrophic agonists prevented phosphorylation of CycD2-target Rb (retinoblastoma gene product) in vitro, and mice deficient for Rb had potentiated hypertrophic growth. Hypertrophic growth requires new protein synthesis and transcription of tRNA genes by RNA polymerase (pol) III, which increases with hypertrophic signals. This load-induced increase in RNA pol III activity is augmented in Rb-deficient hearts. Rb binds and represses Brf-1 and TATA box binding protein (TBP), subunits of RNA pol III–specific transcription factor B, in adult myocardium under basal conditions. However, this association is disrupted in response to transverse aortic constriction. RNA pol III activity is unchanged in CycD2^–/– myocardium after transverse aortic constriction, and there is no dissociation of TBP from Rb. These investigations identify an essential role for the CycD2-Rb pathway as a governor of cardiac myocyte enlargement in response to biomechanical stress and, more fundamentally, as a regulator of the load-induced activation of RNA pol III.

Key Words: hypertrophy • genetically altered mice • animal models of human disease • cell signaling/signal transduction