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  • The EMBO Journal (2006) 25, 3869 - 3879
  • doi:10.1038/sj.emboj.7601252

Published online: 10 August 2006

Hypertrophic growth in cardiac myocytes is mediated by Myc through a Cyclin D2-dependent pathway

Weiguang Zhong1, Songyan Mao1, Scott Tobis1, Ekaterini Angelis1, Maria C Jordan2, Kenneth P Roos2, Michael C Fishbein3, Ignacio Moreno de Alborán4,5 and W Robb MacLellan1,2

  1. The Cardiovascular Research Laboratories, Department of Medicine, UCLA School of Medicine, Los Angeles, California, USA
  2. The Cardiovascular Research Laboratories, Department of Physiology, UCLA School of Medicine, Los Angeles, California, USA
  3. The Cardiovascular Research Laboratories, Department of Pathology, UCLA School of Medicine, Los Angeles, California, USA
  4. Department of Immunology, National Center for Biotechnology, Madrid, Spain
  5. Department of Oncology, National Center for Biotechnology, Madrid, Spain

Correspondence to:

W Robb MacLellan, Departments of Medicine–Cardiology, Cardiovascular Research Laboratories, UCLA School of Medicine, 675 CE Young Dr, MRL 3-645, Los Angeles, CA 90095-1760, USA. Tel.: +1 310 825 2556; Fax: +1 310 206 5777; E-mail: rmaclellan@mednet.ucla.edu

Received 12 January 2006; Accepted 4 July 2006

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.

  • Keywords:

    • cardiac growth,
    • cardiac muscle,
    • cell cycle,
    • hypertrophy,
    • Myc