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Molecular and Cellular Biology, March 2005, p. 2486-2497, Vol. 25, No. 6
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.6.2486-2497.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Overlapping Roles of Pocket Proteins in the Myocardium Are Unmasked by Germ Line Deletion of p130 plus Heart-Specific Deletion of Rb

W. R. MacLellan,1,2,3* A. Garcia,1,3 H. Oh,4 P. Frenkel,4 M. C. Jordan,2 K. P. Roos,2 and M. D. Schneider4

Cardiovascular Research Laboratory and Departments of,1 Medicine,3 Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California,2 Center for Cardiovascular Development, Departments of Medicine, Molecular and Cellular Biology, and Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas4

Received 27 August 2004/ Returned for modification 10 December 2004/ Accepted 15 December 2004

The pocket protein family of tumor suppressors, and Rb specifically, have been implicated as controlling terminal differentiation in many tissues, including the heart. To establish the biological functions of Rb in the heart and overcome the early lethality caused by germ line deletion of Rb, we used a Cre/loxP system to create conditional, heart-specific Rb-deficient mice. Mice that are deficient in Rb exclusively in cardiac myocytes (CRbL/L) are born with the expected Mendelian distribution, and the adult mice displayed no change in heart size, myocyte cell cycle distribution, myocyte apoptosis, or mechanical function. Since both Rb and p130 are expressed in the adult myocardium, we created double-knockout mice (CRbL/L p130–/–) to determine it these proteins have a shared role in regulating cardiac myocyte cell cycle progression. Adult CRbL/L p130–/– mice demonstrated a threefold increase in the heart weight-to-body weight ratio and showed increased numbers of bromodeoxyuridine- and phosphorylated histone H3-positive nuclei, consistent with persistent myocyte cycling. Likewise, the combined deletion of Rb plus p130 up-regulated myocardial expression of Myc, E2F-1, and G1 cyclin-dependent kinase activities, synergistically. Thus, Rb and p130 have overlapping functional roles in vivo to suppress cell cycle activators, including Myc, and maintain quiescence in postnatal cardiac muscle.

* Corresponding author. Mailing address: Cardiovascular Research Laboratory, David Geffen School of Medicine at UCLA, 675 C. E. Young Dr., MRL 3-645, Los Angeles, CA 90095-1760. Phone: (310) 825-2556. Fax: (310) 206-5777. E-mail: rmaclellan{at}mednet.ucla.edu.

Molecular and Cellular Biology, March 2005, p. 2486-2497, Vol. 25, No. 6
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.6.2486-2497.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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