title: Overlapping roles of pocket proteins in the myocardium are unmasked by germ line deletion of p130 plus heart-specific deletion of Rb.
abstract: 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.
authors.affiliation: 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
authors.forename: W R
authors.initials: WR
authors.lastname: MacLellan
authors.forename: A
authors.initials: A
authors.lastname: Garcia
authors.forename: H
authors.initials: H
authors.lastname: Oh
authors.forename: P
authors.initials: P
authors.lastname: Frenkel
authors.forename: M C
authors.initials: MC
authors.lastname: Jordan
authors.forename: K P
authors.initials: KP
authors.lastname: Roos
authors.forename: M D
authors.initials: MD
authors.lastname: Schneider
mesh_terms: 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
chemical_list: 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
references.citation: Science. 2002 Dec 13;298(5601):2188-90
references.pmid: 12481136
references.citation: Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):465-9
references.pmid: 8552662
references.citation: Oncogene. 1992 Mar;7(3):411-21
references.pmid: 1549358
references.citation: Oncogene. 1997 Apr 17;14(15):1789-97
references.pmid: 9150384
references.citation: J Clin Invest. 1997 Jul 1;100(1):169-79
references.pmid: 9202069
references.citation: J Clin Invest. 1997 Dec 1;100(11):2722-8
references.pmid: 9389735
references.citation: Nutr Metab Cardiovasc Dis. 2003 Oct;13(5):291-300
references.pmid: 14717062
references.citation: Genes Dev. 1996 Nov 1;10(21):2794-804
references.pmid: 8946919
references.citation: Am J Physiol. 1997 Jan;272(1 Pt 2):H220-6
references.pmid: 9038941
references.citation: Genes Dev. 1989 Apr;3(4):527-36
references.pmid: 2721961
references.citation: Nature. 2003 Jul 10;424(6945):223-8
references.pmid: 12853964
references.citation: Cell. 1993 Feb 12;72(3):309-24
references.pmid: 8381715
references.citation: Genes Dev. 1999 Jan 15;13(2):142-5
references.pmid: 9925637
references.citation: J Biol Chem. 2001 Jun 8;276(23):20482-90
references.pmid: 11279041
references.citation: Development. 1998 Dec;125(23):4669-79
references.pmid: 9806916
references.citation: Proc Natl Acad Sci U S A. 2000 Sep 26;97(20):10820-5
references.pmid: 10995475
references.citation: Am J Physiol. 1992 Jun;262(6 Pt 2):H1867-76
references.pmid: 1377879
references.citation: Nature. 1992 Sep 24;359(6393):288-94
references.pmid: 1406932
references.citation: Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):2878-83
references.pmid: 11854453
references.citation: Nature. 1992 Sep 24;359(6393):295-300
references.pmid: 1406933
references.citation: J Cell Biol. 1996 Oct;135(2):441-56
references.pmid: 8896600
references.citation: Oncogene. 1999 Dec 20;18(55):7873-82
references.pmid: 10630640
references.citation: J Cell Biol. 1988 Nov;107(5):1911-8
references.pmid: 3182941
references.citation: Oncogene. 1999 Mar 18;18(11):2003-14
references.pmid: 10208422
references.citation: Genes Dev. 1998 Jun 1;12(11):1599-609
references.pmid: 9620848
references.citation: Mol Cell Biol. 2000 Dec;20(23):8903-15
references.pmid: 11073990
references.citation: Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12313-8
references.pmid: 14530411
references.citation: Nat Rev Mol Cell Biol. 2002 Aug;3(8):566-74
references.pmid: 12154368
references.citation: Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):14881-6
references.pmid: 14630948
references.citation: Mol Cell Biol. 2000 May;20(10):3497-509
references.pmid: 10779339
references.citation: Circ Res. 2001 Dec 7;89(12):1122-9
references.pmid: 11739276
references.citation: Oncogene. 1993 Oct;8(10):2659-72
references.pmid: 8378078
references.citation: Genes Dev. 1996 Jul 1;10(13):1633-44
references.pmid: 8682294
references.citation: EMBO J. 1996 Nov 15;15(22):6178-88
references.pmid: 8947040
references.citation: Nature. 1992 Sep 24;359(6393):328-30
references.pmid: 1406937
references.citation: Front Biosci. 1998 Feb 15;3:d250-68
references.pmid: 9468463
references.citation: Genes Dev. 2000 Apr 15;14(8):994-1004
references.pmid: 10783170
references.citation: Mol Cell Biol. 2003 Feb;23(3):1044-53
references.pmid: 12529408
references.citation: J Clin Invest. 1997 Jun 1;99(11):2644-54
references.pmid: 9169494
references.citation: Circ Res. 2001 Mar 30;88(6):587-92
references.pmid: 11282892
references.citation: Am J Physiol. 1996 Nov;271(5 Pt 2):H2183-9
references.pmid: 8945939
references.citation: Science. 1988 Feb 26;239(4843):1029-33
references.pmid: 2964082
references.citation: Brain Res Bull. 2001 Jan 15;54(2):187-98
references.pmid: 11275408
references.citation: Curr Biol. 1999 May 6;9(9):449-59
references.pmid: 10322110
references.citation: Annu Rev Physiol. 2000;62:289-319
references.pmid: 10845093
references.citation: Mol Cell Biol. 1986 Nov;6(11):4140-3
references.pmid: 3796601
references.citation: Mol Cell Biol. 2001 Oct;21(20):6820-32
references.pmid: 11564866
references.citation: J Mol Cell Cardiol. 1998 Mar;30(3):563-78
references.pmid: 9515032
references.citation: Mol Cell. 2001 Jul;8(1):105-13
references.pmid: 11511364
references.citation: Oncogene. 1998 Jul 9;17(1):1-12
references.pmid: 9671308
references.citation: Am J Physiol. 1994 Apr;266(4 Pt 2):H1439-45
references.pmid: 8184922
references.citation: Cell. 2003 Sep 19;114(6):763-76
references.pmid: 14505575
references.citation: J Biol Chem. 1995 Apr 7;270(14):7791-4
references.pmid: 7713869
references.citation: Genes Dev. 1996 Jul 1;10(13):1621-32
references.pmid: 8682293
references.citation: Science. 1994 Jun 3;264(5164):1467-71
references.pmid: 8197461
references.citation: Ann N Y Acad Sci. 1995 Mar 27;752:72-9
references.pmid: 7755297
references.citation: J Cell Sci. 1996 Feb;109 ( Pt 2):397-407
references.pmid: 8838663
references.citation: Oncogene. 2004 Jan 22;23(3):814-23
references.pmid: 14737116
references.citation: Circ Res. 2001 Mar 2;88(4):443-50
references.pmid: 11230113