Overlapping roles of pocket proteins in the myocardium are unmasked by germ line deletion of p130 plus heart-specific deletion of Rb.
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.
MacLellan
W R
WR
Cardiovascular Research Laboratory, David Geffen School of Medicine at UCLA, 675 C. E. Young Dr., MRL 3-645, Los Angeles, CA 90095-1760, USA. rmaclellan@mednet.ucla.edu
Garcia
A
A
Oh
H
H
Frenkel
P
P
Jordan
M C
MC
Roos
K P
KP
Schneider
M D
MD
D000818:Animals; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D056746:Cyclin G; D056766:Cyclin G1; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D017353:Gene Deletion; D018095:Germ-Line Mutation; D006657:Histones / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009206:Myocardium / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011506:Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D050717:Retinoblastoma-Like Protein p130; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology; D015854:Up-Regulation
C534703:Ccng1 protein, mouse; D018797:Cell Cycle Proteins; D056746:Cyclin G; D056766:Cyclin G1; D016213:Cyclins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D006657:Histones; C489428:Myc protein, mouse; D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc; C493838:Rbl2 protein, mouse; D016160:Retinoblastoma Protein; D050717:Retinoblastoma-Like Protein p130; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D018844:Cyclin-Dependent Kinases
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