Hypertrophic growth in cardiac myocytes is mediated by Myc through a Cyclin D2-dependent pathway.
c-Myc (Myc) is highly expressed in developing embryos where it regulates body size by controlling proliferation but not cell size. However, Myc is also induced in many postmitotic tissues, including adult myocardium, in response to stress where the predominant form of growth is an increase in cell size (hypertrophy) and not number. The function of Myc induction in this setting is unproven. Therefore, to explore Myc's role in hypertrophic growth, we created mice where Myc can be inducibly inactivated, specifically in adult myocardium. Myc-deficient hearts demonstrated attenuated stress-induced hypertrophic growth, secondary to a reduction in cell growth of individual myocytes. To explore the dependence of Myc-induced cell growth on CycD2, we created bigenic mice where Myc can be selectively activated in CycD2-null adult myocardium. Myc-dependent hypertrophic growth and cell cycle reentry is blocked in CycD2-deficient hearts. However, in contrast to Myc-induced DNA synthesis, hypertrophic growth is independent of CycD2-induced Cdk2 activity. These data suggest that Myc is required for a normal hypertrophic response and that its growth-promoting effects are also mediated through a CycD2-dependent pathway.
Zhong
Weiguang
W
The Cardiovascular Research Laboratories, Department of Medicine, UCLA School of Medicine, Los Angeles, California, USA.
Mao
Songyan
S
Tobis
Scott
S
Angelis
Ekaterini
E
Jordan
Maria C
MC
Roos
Kenneth P
KP
Fishbein
Michael C
MC
de Alborán
Ignacio Moreno
IM
MacLellan
W Robb
WR
D000818:Animals; D017209:Apoptosis; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle; D049108:Cell Enlargement; D049109:Cell Proliferation; D002478:Cells, Cultured; D056742:Cyclin D2; D016213:Cyclins / Q000235:genetics / Q000502:physiology*; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology* / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000502:physiology*
C486196:Ccnd2 protein, mouse; D056742:Cyclin D2; D016213:Cyclins; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D007545:Isoproterenol