title: A cyclin D2-Rb pathway regulates cardiac myocyte size and RNA polymerase III after biomechanical stress in adult myocardium.
abstract: 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 G(1) 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.
authors.affiliation: The Cardiovascular Research Laboratory, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1760, USA.
authors.forename: Ekaterini
authors.initials: E
authors.lastname: Angelis
authors.forename: Alejandro
authors.initials: A
authors.lastname: Garcia
authors.forename: Shing S
authors.initials: SS
authors.lastname: Chan
authors.forename: Katja
authors.initials: K
authors.lastname: Schenke-Layland
authors.forename: Shuxen
authors.initials: S
authors.lastname: Ren
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Goodfellow
authors.forename: Maria C
authors.initials: MC
authors.lastname: Jordan
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Roos
authors.forename: Robert J
authors.initials: RJ
authors.lastname: White
authors.forename: W Robb
authors.initials: WR
authors.lastname: MacLellan
mesh_terms: D000367:Age Factors; D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology; D048429:Cell Size; D002478:Cells, Cultured; D056742:Cyclin D2; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D050687:E2F1 Transcription Factor / Q000378:metabolism; D050699:E2F3 Transcription Factor / Q000378:metabolism; D050704:E2F4 Transcription Factor / Q000378:metabolism; D050700:E2F5 Transcription Factor / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology*; D010766:Phosphorylation; D012320:RNA Polymerase III / Q000378:metabolism*; D051381:Rats; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013314:Stress, Mechanical
chemical_list: C486196:Ccnd2 protein, mouse; D056742:Cyclin D2; D016213:Cyclins; D050687:E2F1 Transcription Factor; D050699:E2F3 Transcription Factor; D050704:E2F4 Transcription Factor; D050700:E2F5 Transcription Factor; C493754:E2f1 protein, mouse; C490840:E2f3 protein, mouse; C493763:E2f4 protein, mouse; C490490:E2f5 protein, mouse; D016160:Retinoblastoma Protein; D012320:RNA Polymerase III