Home LiteratureArticle Details
PMID: 17429040 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review

Cardiac myocyte cell cycle control in development, disease, and regeneration.

Physiological reviews ·Vol. 87 ·No. 2 ·2007-04-00 ·Pages 521-44

Ahuja P, Sdek P, MacLellan WR

Abstract

Cardiac myocytes rapidly proliferate during fetal life but exit the cell cycle soon after birth in mammals. Although the extent to which adult cardiac myocytes are capable of cell cycle reentry is controversial and species-specific differences may exist, it appears that for the vast majority of adult cardiac myocytes the predominant form of growth postnatally is an increase in cell size (hypertrophy) not number. Unfortunately, this limits the ability of the heart to restore function after any significant injury. Interest in novel regenerative therapies has led to the accumulation of much information on the mechanisms that regulate the rapid proliferation of cardiac myocytes in utero, their cell cycle exit in the perinatal period, and the permanent arrest (terminal differentiation) in adult myocytes. The recent identification of cardiac progenitor cells capable of giving rise to cardiac myocyte-like cells has challenged the dogma that the heart is a terminally differentiated organ and opened new prospects for cardiac regeneration. In this review, we summarize the current understanding of cardiomyocyte cell cycle control in normal development and disease. In addition, we also discuss the potential usefulness of cardiomyocyte self-renewal as well as feasibility of therapeutic manipulation of the cardiac myocyte cell cycle for cardiac regeneration.

MeSH Terms
Animals Cardiomegaly/physiopathology Cell Cycle/physiology Cell Proliferation Heart/growth & development Heart Diseases/pathology,physiopathology Humans Myocytes, Cardiac/physiology Regeneration/physiology
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Ahuja Preeti
Division of Cardiology, University of California at Los Angeles, The Cardiovascular Research Laboratory, Department of Medicine, David Geffen School of Medicine 90095-1760, USA.
Sdek Patima
MacLellan W Robb
References (252)
252 references, click to expand
  1. Protooncogene induction and reprogramming of cardiac gene expression produced by pressure overload.
    Proc Natl Acad Sci U S A. 1988 Jan;85(2):339-43 PMID: 2963328
  2. Comparison of mitosis in binucleated and mononucleated newt cardiac myocytes.
    Anat Rec. 1998 Jun;251(2):245-55 PMID: 9624456
  3. Targeted inhibition of p38 MAPK promotes hypertrophic cardiomyopathy through upregulation of calcineurin-NFAT signaling.
    J Clin Invest. 2003 May;111(10):1475-86 PMID: 12750397
  4. Unchain my heart: the scientific foundations of cardiac repair.
    J Clin Invest. 2005 Mar;115(3):572-83 PMID: 15765139
  5. Regulation of RNA polymerase III transcription during hypertrophic growth.
    EMBO J. 2006 Apr 5;25(7):1522-33 PMID: 16541106
  6. c-Myc regulates mammalian body size by controlling cell number but not cell size.
    Nature. 2001 Dec 13;414(6865):768-73 PMID: 11742404
  7. p38 mitogen-activated protein kinase activation is required for fibroblast growth factor-2-stimulated cell proliferation but not differentiation.
    J Biol Chem. 1999 Jun 18;274(25):17491-8 PMID: 10364180
  8. E2F-8: an E2F family member with a similar organization of DNA-binding domains to E2F-7.
    Oncogene. 2005 Jul 21;24(31):5000-4 PMID: 15897886
  9. Oncogenic capacity of the E2F1 gene.
    Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12823-7 PMID: 7809128
  10. Expression and activities of cyclins and cyclin-dependent kinases in developing rat ventricular myocytes.
    J Mol Cell Cardiol. 1997 Aug;29(8):2261-71 PMID: 9281457
  11. Sequential myofibrillar breakdown accompanies mitotic division of mammalian cardiomyocytes.
    J Cell Sci. 2004 Jul 1;117(Pt 15):3295-306 PMID: 15226401
  12. Dynamic changes of gene expression profiles during postnatal development of the heart in mice.
    Heart. 2004 Aug;90(8):927-34 PMID: 15253972
  13. Number of nuclei in isolated myocardial cells of pigs.
    Virchows Arch B Cell Pathol. 1974;15(4):279-94 PMID: 4135954
  14. Overlapping roles of pocket proteins in the myocardium are unmasked by germ line deletion of p130 plus heart-specific deletion of Rb.
    Mol Cell Biol. 2005 Mar;25(6):2486-97 PMID: 15743840
  15. Identification and characterization of the tuberous sclerosis gene on chromosome 16.
    Cell. 1993 Dec 31;75(7):1305-15 PMID: 8269512
  16. The IGF-1-IGF-1 receptor system modulates myocyte proliferation but not myocyte cellular hypertrophy in vitro.
    Exp Cell Res. 1994 Dec;215(2):273-83 PMID: 7982470
  17. Mouse development and cell proliferation in the absence of D-cyclins.
    Cell. 2004 Aug 20;118(4):477-91 PMID: 15315760
  18. Shared role of the pRB-related p130 and p107 proteins in limb development.
    Genes Dev. 1996 Jul 1;10(13):1633-44 PMID: 8682294
  19. A null c-myc mutation causes lethality before 10.5 days of gestation in homozygotes and reduced fertility in heterozygous female mice.
    Genes Dev. 1993 Apr;7(4):671-82 PMID: 8458579
  20. Cooperation of p38 and extracellular signal-regulated kinase mitogen-activated protein kinase pathways during granulocyte colony-stimulating factor-induced hemopoietic cell proliferation.
    J Biol Chem. 1999 Feb 12;274(7):4096-105 PMID: 9933603
  21. Cyclin A2 mediates cardiomyocyte mitosis in the postmitotic myocardium.
    J Biol Chem. 2004 Aug 20;279(34):35858-66 PMID: 15159393
  22. Heart regeneration in adult MRL mice.
    Proc Natl Acad Sci U S A. 2001 Aug 14;98(17):9830-5 PMID: 11493713
  23. Cardiac-specific overexpression of cyclin-dependent kinase 2 increases smaller mononuclear cardiomyocytes.
    Circ Res. 2001 Mar 2;88(4):443-50 PMID: 11230113
  24. Identification of c-MYC as a target of the APC pathway.
    Science. 1998 Sep 4;281(5382):1509-12 PMID: 9727977
  25. Expressions and activities of cell cycle regulatory molecules during the transition from myocyte hyperplasia to hypertrophy.
    J Mol Cell Cardiol. 1998 Oct;30(10):2121-35 PMID: 9799664
  26. FGF1/p38 MAP kinase inhibitor therapy induces cardiomyocyte mitosis, reduces scarring, and rescues function after myocardial infarction.
    Proc Natl Acad Sci U S A. 2006 Oct 17;103(42):15546-51 PMID: 17032753
  27. The retinoblastoma protein binds to a family of E2F transcription factors.
    Mol Cell Biol. 1993 Dec;13(12):7813-25 PMID: 8246996
  28. Strain-dependent embryonic lethality in mice lacking the retinoblastoma-related p130 gene.
    Development. 1998 Dec;125(23):4669-79 PMID: 9806916
  29. Formation of binucleated cardiac myocytes in rat heart: I. Role of actin-myosin contractile ring.
    J Mol Cell Cardiol. 1997 Jun;29(6):1541-51 PMID: 9220340
  30. E2F-1 functions in mice to promote apoptosis and suppress proliferation.
    Cell. 1996 May 17;85(4):549-61 PMID: 8653790
  31. Jumonji regulates cardiomyocyte proliferation via interaction with retinoblastoma protein.
    J Biol Chem. 2005 Sep 2;280(35):30916-23 PMID: 15870077
  32. p38 MAP kinase inhibition enables proliferation of adult mammalian cardiomyocytes.
    Genes Dev. 2005 May 15;19(10):1175-87 PMID: 15870258
  33. Myofibrillogenesis in the developing chicken heart: assembly of Z-disk, M-line and the thick filaments.
    J Cell Sci. 1999 May;112 ( Pt 10):1529-39 PMID: 10212147
  34. Tumor induction and tissue atrophy in mice lacking E2F-1.
    Cell. 1996 May 17;85(4):537-48 PMID: 8653789
  35. Targeted disruption of p107: functional overlap between p107 and Rb.
    Genes Dev. 1996 Jul 1;10(13):1621-32 PMID: 8682293
  36. Involvement of cyclin D activity in left ventricle hypertrophy in vivo and in vitro.
    Cardiovasc Res. 2002 Oct;56(1):64-75 PMID: 12237167
  37. Reactive synthesis of DNA and mitotiv division in atrial heart muscle cells following ventricle infarction.
    Experientia. 1968 Dec 15;24(12):1234-5 PMID: 5703024
  38. Inhibition of E2F abrogates the development of cardiac myocyte hypertrophy.
    J Biol Chem. 2003 Jun 13;278(24):21388-94 PMID: 12682052
  39. DNA content, ploidy level and number of nuclei in the human heart after myocardial infarction.
    Cardiovasc Res. 1997 Oct;36(1):45-51 PMID: 9415271
  40. N-myc proto-oncogene expression during organogenesis in the developing mouse as revealed by in situ hybridization.
    J Cell Biol. 1988 Oct;107(4):1325-35 PMID: 3049618
  41. DNA synthesis and mitosis in adult amphibian cardiac muscle cells in vitro.
    Science. 1979 Sep 21;205(4412):1281-2 PMID: 472744
  42. HIF-1alpha is essential for myeloid cell-mediated inflammation.
    Cell. 2003 Mar 7;112(5):645-57 PMID: 12628185
  43. An intrinsic timer that controls cell-cycle withdrawal in cultured cardiac myocytes.
    Dev Biol. 1999 Dec 15;216(2):659-70 PMID: 10642800
  44. Connections between growth and the cell cycle.
    Curr Opin Cell Biol. 1998 Dec;10(6):784-90 PMID: 9914170
  45. E2F-1 regulates the expression of a subset of target genes during skeletal myoblast hypertrophy.
    J Biol Chem. 2004 Oct 15;279(42):43625-33 PMID: 15304485
  46. Downregulation of polo-like kinase correlates with loss of proliferative ability of cardiac myocytes.
    J Mol Cell Cardiol. 1997 Mar;29(3):929-37 PMID: 9152854
  47. The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway.
    Proc Natl Acad Sci U S A. 1999 May 11;96(10):5522-7 PMID: 10318916
  48. C-myc protooncogene modulates cardiac hypertrophic growth in transgenic mice.
    Am J Physiol. 1992 Feb;262(2 Pt 2):H590-7 PMID: 1311531
  49. E2F: a link between the Rb tumor suppressor protein and viral oncoproteins.
    Science. 1992 Oct 16;258(5081):424-9 PMID: 1411535
  50. Postnatally induced inactivation of gp130 in mice results in neurological, cardiac, hematopoietic, immunological, hepatic, and pulmonary defects.
    J Exp Med. 1998 Nov 16;188(10):1955-65 PMID: 9815272
  51. The Drosophila mitochondrial ribosomal protein mRpL12 is required for Cyclin D/Cdk4-driven growth.
    EMBO J. 2005 Feb 9;24(3):623-34 PMID: 15692573
  52. Cardiac muscle cell hypertrophy and apoptosis induced by distinct members of the p38 mitogen-activated protein kinase family.
    J Biol Chem. 1998 Jan 23;273(4):2161-8 PMID: 9442057
  53. E2F4 actively promotes the initiation and maintenance of nerve growth factor-induced cell differentiation.
    Mol Cell Biol. 1999 Sep;19(9):6048-56 PMID: 10454552
  54. Retinoblastoma protein directly interacts with and activates the transcription factor NF-IL6.
    Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):465-9 PMID: 8552662
  55. Enhanced cardiomyocyte DNA synthesis during myocardial hypertrophy in mice expressing a modified TSC2 transgene.
    Circ Res. 2000 May 26;86(10):1069-77 PMID: 10827137
  56. E2F-4 switches from p130 to p107 and pRB in response to cell cycle reentry.
    Mol Cell Biol. 1996 Apr;16(4):1436-49 PMID: 8657117
  57. Fibroblast growth factor receptor is required for in vivo cardiac myocyte proliferation at early embryonic stages of heart development.
    Proc Natl Acad Sci U S A. 1995 Jan 17;92(2):467-71 PMID: 7831312
  58. Therapeutic delivery of cyclin A2 induces myocardial regeneration and enhances cardiac function in ischemic heart failure.
    Circulation. 2006 Jul 4;114(1 Suppl):I206-13 PMID: 16820573
  59. Dissociated expression of c-myc and a fos-related competence gene during cardiac myogenesis.
    Mol Cell Biol. 1986 Nov;6(11):4140-3 PMID: 3796601
  60. Cytokinesis: the great divide.
    Trends Cell Biol. 2005 Jan;15(1):1 PMID: 15653070
  61. Interaction of myogenic factors and the retinoblastoma protein mediates muscle cell commitment and differentiation.
    Cell. 1993 Feb 12;72(3):309-24 PMID: 8381715
  62. N-myc can functionally replace c-myc in murine development, cellular growth, and differentiation.
    Genes Dev. 2000 Jun 1;14(11):1390-9 PMID: 10837031
  63. p38 and extracellular signal-regulated kinases regulate the myogenic program at multiple steps.
    Mol Cell Biol. 2000 Jun;20(11):3951-64 PMID: 10805738
  64. Functional abrogation of p53 is required for T-Ag induced proliferation in cardiomyocytes.
    J Mol Cell Cardiol. 2001 Aug;33(8):1405-19 PMID: 11448130
  65. Inducible activation of c-Myc in adult myocardium in vivo provokes cardiac myocyte hypertrophy and reactivation of DNA synthesis.
    Circ Res. 2001 Dec 7;89(12):1122-9 PMID: 11739276
  66. Survey of studies examining mammalian cardiomyocyte DNA synthesis.
    Circ Res. 1998 Jul 13;83(1):15-26 PMID: 9670914
  67. The tuberous sclerosis genes and regulation of the cyclin-dependent kinase inhibitor p27.
    Mutat Res. 2006 Sep;613(1):10-6 PMID: 16713332
  68. Assessment of cardiomyocyte DNA synthesis during hypertrophy in adult mice.
    Am J Physiol. 1994 Apr;266(4 Pt 2):H1439-45 PMID: 8184922
  69. c-Myc target genes involved in cell growth, apoptosis, and metabolism.
    Mol Cell Biol. 1999 Jan;19(1):1-11 PMID: 9858526
  70. Cell cycle exit upon myogenic differentiation.
    Curr Opin Genet Dev. 1997 Oct;7(5):597-602 PMID: 9388774
  71. Cardiac rhabdomyomas in tuberous sclerosis.
    Ann N Y Acad Sci. 1991;615:50-7 PMID: 2039167
  72. Loss of the imprinted IGF2/cation-independent mannose 6-phosphate receptor results in fetal overgrowth and perinatal lethality.
    Genes Dev. 1994 Dec 15;8(24):2953-63 PMID: 8001817
  73. Distinct roles for E2F proteins in cell growth control and apoptosis.
    Proc Natl Acad Sci U S A. 1997 Jul 8;94(14):7245-50 PMID: 9207076
  74. Downregulation of cyclin-dependent kinase inhibitors p21 and p27 in pressure-overload hypertrophy.
    Am J Physiol. 1997 Sep;273(3 Pt 2):H1358-67 PMID: 9321826
  75. Differential and dramatic changes of cyclin-dependent kinase activities in cardiomyocytes during the neonatal period.
    J Mol Cell Cardiol. 1997 Jul;29(7):1767-77 PMID: 9236132
  76. Activation and function of cyclin T-Cdk9 (positive transcription elongation factor-b) in cardiac muscle-cell hypertrophy.
    Nat Med. 2002 Nov;8(11):1310-7 PMID: 12368904
  77. Cyclin D1 expression is regulated positively by the p42/p44MAPK and negatively by the p38/HOGMAPK pathway.
    J Biol Chem. 1996 Aug 23;271(34):20608-16 PMID: 8702807
  78. Hypoxic activation of the atrial natriuretic peptide gene promoter through direct and indirect actions of hypoxia-inducible factor-1.
    Biochem J. 2003 Feb 15;370(Pt 1):149-57 PMID: 12413399
  79. Early expression of myocardial HIF-1alpha in response to mechanical stresses: regulation by stretch-activated channels and the phosphatidylinositol 3-kinase signaling pathway.
    Circ Res. 2002 Feb 8;90(2):E25-33 PMID: 11834720
  80. Interrelations of the proliferation and differentiation processes during cardiact myogenesis and regeneration.
    Int Rev Cytol. 1977;51:186-273 PMID: 338537
  81. Evidence of myocyte hyperplasia in hypertrophic cardiomyopathy and other disorders with myocardial hypertrophy?
    Z Kardiol. 1987;76 Suppl 3:20-5 PMID: 2963448
  82. Proliferation in vivo and in culture of differentiated adult atrial cardiomyocytes from transgenic mice.
    Am J Physiol. 1990 Dec;259(6 Pt 2):H1826-34 PMID: 2175567
  83. Expression patterns of the E2F family of transcription factors during mouse nervous system development.
    Mech Dev. 1997 Aug;66(1-2):13-25 PMID: 9376316
  84. fgfr-1 is required for embryonic growth and mesodermal patterning during mouse gastrulation.
    Genes Dev. 1994 Dec 15;8(24):3032-44 PMID: 8001822
  85. Characterisation and regulation of E2F-6 and E2F-6b in the rat heart: a potential target for myocardial regeneration?
    J Pharm Pharmacol. 2006 Jan;58(1):73-82 PMID: 16393466
  86. The Drosophila cyclin D-Cdk4 complex promotes cellular growth.
    EMBO J. 2000 Sep 1;19(17):4543-54 PMID: 10970848
  87. Adenoviral delivery of E2F-1 directs cell cycle reentry and p53-independent apoptosis in postmitotic adult myocardium in vivo.
    J Clin Invest. 1997 Dec 1;100(11):2722-8 PMID: 9389735
  88. Activation and signaling of the p38 MAP kinase pathway.
    Cell Res. 2005 Jan;15(1):11-8 PMID: 15686620
  89. Adenovirus E1A represses cardiac gene transcription and reactivates DNA synthesis in ventricular myocytes, via alternative pocket protein- and p300-binding domains.
    J Biol Chem. 1995 Apr 7;270(14):7791-4 PMID: 7713869
  90. Low molecular weight inhibitors of Myc-Max interaction and function.
    Oncogene. 2003 Sep 18;22(40):6151-9 PMID: 13679853
  91. Drosophila myc regulates cellular growth during development.
    Cell. 1999 Sep 17;98(6):779-90 PMID: 10499795
  92. Persistent expression of the ATP-binding cassette transporter, Abcg2, identifies cardiac SP cells in the developing and adult heart.
    Dev Biol. 2004 Jan 1;265(1):262-75 PMID: 14697368
  93. Cellular signaling by fibroblast growth factor receptors.
    Cytokine Growth Factor Rev. 2005 Apr;16(2):139-49 PMID: 15863030
  94. Characterization of transcription factor E2F complexes during muscle and neuronal differentiation.
    Oncogene. 1995 Sep 7;11(5):909-20 PMID: 7675450
  95. Stimulation of proliferative events in the adult amphibian cardiac myocyte.
    Ann N Y Acad Sci. 1995 Mar 27;752:30-46 PMID: 7755274
  96. Telomere shortening is an in vivo marker of myocyte replication and aging.
    Am J Pathol. 2000 Mar;156(3):813-9 PMID: 10702397
  97. Gp130 and the interleukin-6 family of cytokines.
    Annu Rev Immunol. 1997;15:797-819 PMID: 9143707
  98. Divergent siblings: E2F2 and E2F4 but not E2F1 and E2F3 induce DNA synthesis in cardiomyocytes without activation of apoptosis.
    Circ Res. 2005 Mar 18;96(5):509-17 PMID: 15718499
  99. G1 phase progression: cycling on cue.
    Cell. 1994 Nov 18;79(4):551-5 PMID: 7954821
  100. Expression of cyclin D1 and CDK4 causes hypertrophic growth of cardiomyocytes in culture: a possible implication for cardiac hypertrophy.
    Biochem Biophys Res Commun. 2002 Aug 16;296(2):274-80 PMID: 12163013
  101. Infertility in female mice lacking the receptor for interleukin 11 is due to a defective uterine response to implantation.
    Nat Med. 1998 Mar;4(3):303-8 PMID: 9500603
  102. LEK1 is a potential inhibitor of pocket protein-mediated cellular processes.
    J Biol Chem. 2004 Jan 2;279(1):664-76 PMID: 14555653
  103. Redefining the roles of p38 and JNK signaling in cardiac hypertrophy: dichotomy between cultured myocytes and animal models.
    J Mol Cell Cardiol. 2003 Dec;35(12):1385-94 PMID: 14654364
  104. Acquisition of multiple nuclei and the activity of DNA polymerase alpha and reinitiation of DNA replication in terminally differentiated adult cardiac muscle cells in culture.
    Dev Biol. 1983 Oct;99(2):331-7 PMID: 6618006
  105. Cardiac myocyte hypertrophy is associated with c-myc protooncogene expression.
    Proc Natl Acad Sci U S A. 1986 Nov;83(21):8348-50 PMID: 3022291
  106. E2F-5, a new E2F family member that interacts with p130 in vivo.
    Mol Cell Biol. 1995 Jun;15(6):3082-9 PMID: 7760804
  107. Specificity of E2F1, E2F2, and E2F3 in mediating phenotypes induced by loss of Rb.
    Cell Growth Differ. 2002 May;13(5):215-25 PMID: 12065245
  108. Cytoplasmic signaling pathways that regulate cardiac hypertrophy.
    Annu Rev Physiol. 2001;63:391-426 PMID: 11181961
  109. Intense myocyte formation from cardiac stem cells in human cardiac hypertrophy.
    Proc Natl Acad Sci U S A. 2003 Sep 2;100(18):10440-5 PMID: 12928492
  110. Mitoses and binucleated cells in perinatal human hearts.
    Virchows Arch B Cell Pathol Incl Mol Pathol. 1985;48(1):59-67 PMID: 2858939
  111. Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction.
    Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12313-8 PMID: 14530411
  112. Mice lacking cyclin D1 are small and show defects in eye and mammary gland development.
    Genes Dev. 1995 Oct 1;9(19):2364-72 PMID: 7557388
  113. Aging, cardiac hypertrophy and ischemic cardiomyopathy do not affect the proportion of mononucleated and multinucleated myocytes in the human heart.
    J Mol Cell Cardiol. 1996 Jul;28(7):1463-77 PMID: 8841934
  114. Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart.
    Dev Cell. 2003 Dec;5(6):877-89 PMID: 14667410
  115. Tissue-specific regulation of the alpha-myosin heavy chain gene promoter in transgenic mice.
    J Biol Chem. 1991 Dec 25;266(36):24613-20 PMID: 1722208
  116. Probing the role of septins in cardiomyocytes.
    Exp Cell Res. 2006 May 15;312(9):1598-609 PMID: 16739252
  117. Interplay between the retinoblastoma protein and LEK1 specifies stem cells toward the cardiac lineage.
    EMBO J. 2005 May 4;24(9):1750-61 PMID: 15861132
  118. Endocardial and epicardial derived FGF signals regulate myocardial proliferation and differentiation in vivo.
    Dev Cell. 2005 Jan;8(1):85-95 PMID: 15621532
  119. Role of insulin-like growth factors in embryonic and postnatal growth.
    Cell. 1993 Oct 8;75(1):73-82 PMID: 8402902
  120. Myocyte proliferation in end-stage cardiac failure in humans.
    Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8801-5 PMID: 9671759
  121. E2F-1 and E2F-3 are functionally distinct in their ability to promote myeloid cell cycle progression and block granulocyte differentiation.
    Cell Growth Differ. 1998 Jan;9(1):59-69 PMID: 9438389
  122. Triggering p53 after cytokinesis failure.
    J Cell Biol. 2004 Jun 7;165(5):607-8 PMID: 15184396
  123. Wnt signaling: is the party in the nucleus?
    Genes Dev. 2006 Jun 1;20(11):1394-404 PMID: 16751178
  124. The conserved phosphoinositide 3-kinase pathway determines heart size in mice.
    EMBO J. 2000 Jun 1;19(11):2537-48 PMID: 10835352
  125. Ink4a/Arf expression is a biomarker of aging.
    J Clin Invest. 2004 Nov;114(9):1299-307 PMID: 15520862
  126. Transcriptional effects of chronic Akt activation in the heart.
    J Biol Chem. 2002 Jun 21;277(25):22528-33 PMID: 11956204
  127. Adult cardiac stem cells are multipotent and support myocardial regeneration.
    Cell. 2003 Sep 19;114(6):763-76 PMID: 14505575
  128. Cardiomyocyte DNA synthesis and binucleation during murine development.
    Am J Physiol. 1996 Nov;271(5 Pt 2):H2183-9 PMID: 8945939
  129. Anillin localization defect in cardiomyocyte binucleation.
    J Mol Cell Cardiol. 2006 Oct;41(4):601-12 PMID: 16889791
  130. Akt induces enhanced myocardial contractility and cell size in vivo in transgenic mice.
    Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12333-8 PMID: 12237475
  131. FGF-2 controls the differentiation of resident cardiac precursors into functional cardiomyocytes.
    J Clin Invest. 2005 Jul;115(7):1724-33 PMID: 15951838
  132. The new kid on the block(ade) of the IGF-1 receptor.
    Cancer Cell. 2004 Mar;5(3):201-2 PMID: 15050909
  133. Skeletal muscle cells lacking the retinoblastoma protein display defects in muscle gene expression and accumulate in S and G2 phases of the cell cycle.
    J Cell Biol. 1996 Oct;135(2):441-56 PMID: 8896600
  134. Overexpression of cdk Inhibitor p16INK4a by adenovirus vector inhibits cardiac hypertrophy in vitro and in vivo: a novel strategy for the gene therapy of cardiac hypertrophy.
    J Mol Cell Cardiol. 2001 Aug;33(8):1493-504 PMID: 11448137
  135. Leukaemia inhibitory factor is necessary for maintenance of haematopoietic stem cells and thymocyte stimulation.
    Nature. 1993 May 27;363(6427):361-4 PMID: 8497320
  136. Transcriptional repression of the E2F-1 gene by interferon-alpha is mediated through induction of E2F-4/pRB and E2F-4/p130 complexes.
    Oncogene. 1999 Mar 18;18(11):2003-14 PMID: 10208422
  137. Targeted disruption of gp130, a common signal transducer for the interleukin 6 family of cytokines, leads to myocardial and hematological disorders.
    Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):407-11 PMID: 8552649
  138. High and low molecular weight fibroblast growth factor-2 increase proliferation of neonatal rat cardiac myocytes but have differential effects on binucleation and nuclear morphology. Evidence for both paracrine and intracrine actions of fibroblast growth factor-2.
    Circ Res. 1996 Jan;78(1):126-36 PMID: 8603495
  139. Appendage regeneration in adult vertebrates and implications for regenerative medicine.
    Science. 2005 Dec 23;310(5756):1919-23 PMID: 16373567
  140. Nuclear targeting of Akt enhances ventricular function and myocyte contractility.
    Circ Res. 2005 Dec 9;97(12):1332-41 PMID: 16293788
  141. c-MYC: more than just a matter of life and death.
    Nat Rev Cancer. 2002 Oct;2(10):764-76 PMID: 12360279
  142. A pRb-independent mechanism preserves the postmitotic state in terminally differentiated skeletal muscle cells.
    J Cell Biol. 2004 Nov 8;167(3):417-23 PMID: 15520231
  143. Combined loss of Cdk2 and Cdk4 results in embryonic lethality and Rb hypophosphorylation.
    Dev Cell. 2006 May;10(5):563-73 PMID: 16678773
  144. Inhibitors of mammalian G1 cyclin-dependent kinases.
    Genes Dev. 1995 May 15;9(10):1149-63 PMID: 7758941
  145. Role of G1 phase cyclins and cyclin-dependent kinases during cardiomyocyte hypertrophic growth in rats.
    Am J Physiol. 1998 Sep;275(3 Pt 2):H814-22 PMID: 9724284
  146. Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha.
    Genes Dev. 1998 Jan 15;12(2):149-62 PMID: 9436976
  147. A specific, nonproliferative role for E2F-5 in choroid plexus function revealed by gene targeting.
    Genes Dev. 1998 Apr 15;12(8):1092-8 PMID: 9553039
  148. Regulation of basic fibroblast growth factor (bFGF) and FGF receptors in the heart.
    Ann N Y Acad Sci. 1995 Mar 27;752:353-69 PMID: 7755280
  149. Overexpression of MYC causes p53-dependent G2 arrest of normal fibroblasts.
    Proc Natl Acad Sci U S A. 2000 Sep 12;97(19):10544-8 PMID: 10962037
  150. Elevated blood pressure and enhanced myocardial contractility in mice with severe IGF-1 deficiency.
    J Clin Invest. 1996 Dec 1;98(11):2648-55 PMID: 8958230
  151. The E2F1-3 transcription factors are essential for cellular proliferation.
    Nature. 2001 Nov 22;414(6862):457-62 PMID: 11719808
  152. Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6.
    Cell. 2004 Aug 20;118(4):493-504 PMID: 15315761
  153. Murine FGFR-1 is required for early postimplantation growth and axial organization.
    Genes Dev. 1994 Dec 15;8(24):3045-57 PMID: 8001823
  154. Persistent and heterogenous expression of the cyclin-dependent kinase inhibitor, p27KIP1, in rat hearts during development.
    J Mol Cell Cardiol. 1998 Mar;30(3):463-74 PMID: 9515024
  155. DNA Content in End-Stage Heart Failure.
    Adv Clin Path. 1997 Jan;1(1):59-73 PMID: 10352469
  156. Heart regeneration in zebrafish.
    Science. 2002 Dec 13;298(5601):2188-90 PMID: 12481136
  157. Pocket proteins and cell cycle control.
    Oncogene. 2005 Apr 18;24(17):2796-809 PMID: 15838516
  158. Deregulated transcription factor E2F-1 expression leads to S-phase entry and p53-mediated apoptosis.
    Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):10918-22 PMID: 7971984
  159. p57KIP2, a structurally distinct member of the p21CIP1 Cdk inhibitor family, is a candidate tumor suppressor gene.
    Genes Dev. 1995 Mar 15;9(6):650-62 PMID: 7729684
  160. Cell cycle regulation by p38 MAP kinases.
    Biol Cell. 2001 Sep;93(1-2):47-51 PMID: 11730321
  161. Electrical stimulation of neonatal cardiomyocytes results in the sequential activation of nuclear genes governing mitochondrial proliferation and differentiation.
    Proc Natl Acad Sci U S A. 1997 Oct 14;94(21):11399-404 PMID: 9326621
  162. Forced expression of the cyclin B1-CDC2 complex induces proliferation in adult rat cardiomyocytes.
    Biochem J. 2004 Sep 1;382(Pt 2):411-6 PMID: 15253691
  163. Terminally differentiated neonatal rat myocardial cells proliferate and maintain specific differentiated functions following expression of SV40 large T antigen.
    J Biol Chem. 1988 Dec 15;263(35):19132-6 PMID: 3198615
  164. Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis.
    Nature. 1992 Sep 24;359(6393):288-94 PMID: 1406932
  165. Loss of E2F4 activity leads to abnormal development of multiple cellular lineages.
    Mol Cell. 2000 Aug;6(2):293-306 PMID: 10983977
  166. Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r).
    Cell. 1993 Oct 8;75(1):59-72 PMID: 8402901
  167. c-Myc enhances protein synthesis and cell size during B lymphocyte development.
    Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13180-5 PMID: 10557294
  168. E1A can provoke G1 exit that is refractory to p21 and independent of activating cdk2.
    Circ Res. 1999 Aug 20;85(4):319-28 PMID: 10455060
  169. Ventricular loading is coupled with DNA synthesis in adult cardiac myocytes after acute and chronic myocardial infarction in rats.
    Circ Res. 1992 Dec;71(6):1379-89 PMID: 1423934
  170. Direct activation of RNA polymerase III transcription by c-Myc.
    Nature. 2003 Jan 16;421(6920):290-4 PMID: 12529648
  171. Cyclin D2 induces proliferation of cardiac myocytes and represses hypertrophy.
    Exp Cell Res. 2005 Mar 10;304(1):149-61 PMID: 15707582
  172. Combinatorial roles for pRB, p107, and p130 in E2F-mediated cell cycle control.
    Proc Natl Acad Sci U S A. 2000 Sep 26;97(20):10820-5 PMID: 10995475
  173. Heterogeneous proliferative potential in regenerative adult newt cardiomyocytes.
    J Cell Sci. 2003 Oct 1;116(Pt 19):4001-9 PMID: 12928330
  174. Inhibition of TGFbeta signaling potentiates the FGF-2-induced stimulation of cardiomyocyte DNA synthesis.
    Cardiovasc Res. 2004 Dec 1;64(3):516-25 PMID: 15537505
  175. MRL mice fail to heal the heart in response to ischemia-reperfusion injury.
    Wound Repair Regen. 2005 Mar-Apr;13(2):205-8 PMID: 15828946
  176. A constitutive mutation of ALK5 disrupts cardiac looping and morphogenesis in mice.
    Dev Biol. 1998 Jul 1;199(1):72-9 PMID: 9676193
  177. Simian virus 40 large T antigen binds a novel Bcl-2 homology domain 3-containing proapoptosis protein in the cytoplasm.
    J Biol Chem. 2000 Feb 4;275(5):3239-46 PMID: 10652310
  178. Evidence that human cardiac myocytes divide after myocardial infarction.
    N Engl J Med. 2001 Jun 7;344(23):1750-7 PMID: 11396441
  179. Heterodimerization of the transcription factors E2F-1 and DP-1 is required for binding to the adenovirus E4 (ORF6/7) protein.
    J Virol. 1994 Aug;68(8):5027-35 PMID: 8035503
  180. Assessment of cardiomyocyte DNA synthesis in normal and injured adult mouse hearts.
    Am J Physiol. 1997 Jan;272(1 Pt 2):H220-6 PMID: 9038941
  181. Mutant mouse models reveal the relative roles of E2F1 and E2F3 in vivo.
    Mol Cell Biol. 2002 Apr;22(8):2663-72 PMID: 11909960
  182. DNA synthesis in myocytes from different myocardial compartments of young rats in norm, after experimental infarction and in vitro.
    Biomed Biochim Acta. 1987;46(8-9):S610-5 PMID: 3435518
  183. Retinoblastoma protein positively regulates terminal adipocyte differentiation through direct interaction with C/EBPs.
    Genes Dev. 1996 Nov 1;10(21):2794-804 PMID: 8946919
  184. The c-myc proto-oncogene regulates cardiac development in transgenic mice.
    Mol Cell Biol. 1990 Jul;10(7):3709-16 PMID: 1694017
  185. The molecular requirements for cytokinesis.
    Science. 2005 Mar 18;307(5716):1735-9 PMID: 15774750
  186. The retinoblastoma gene pathway regulates the postmitotic state of hair cells of the mouse inner ear.
    Development. 2005 May;132(10):2377-88 PMID: 15843406
  187. Inhibition of cardiac myocyte division in c-myc transgenic mice.
    J Mol Cell Cardiol. 1997 Jul;29(7):1895-902 PMID: 9236143
  188. TEF-1 and C/EBPbeta are major p38alpha MAPK-regulated transcription factors in proliferating cardiomyocytes.
    Biochem J. 2006 May 15;396(1):163-72 PMID: 16492136
  189. Establishment of cardiac cytoarchitecture in the developing mouse heart.
    Dev Biol. 2006 Jan 15;289(2):430-41 PMID: 16337936
  190. Requirement for a functional Rb-1 gene in murine development.
    Nature. 1992 Sep 24;359(6393):328-30 PMID: 1406937
  191. Rb is required for progression through myogenic differentiation but not maintenance of terminal differentiation.
    J Cell Biol. 2004 Sep 13;166(6):865-76 PMID: 15364961
  192. Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor pVHL.
    Nature. 2003 Sep 18;425(6955):307-11 PMID: 13679920
  193. Essential roles for G1 cyclin-dependent kinase activity in development of cardiomyocyte hypertrophy.
    Am J Physiol. 1998 Dec;275(6 Pt 2):H2036-40 PMID: 9843802
  194. Cell cycle profiles and expressions of p21CIP1 AND P27KIP1 during myocyte development.
    Int J Cardiol. 1998 Dec 1;67(2):133-42 PMID: 9891946
  195. Cardiac regeneration: repopulating the heart.
    Annu Rev Physiol. 2006;68:29-49 PMID: 16460265
  196. Atrial natriuretic factor-SV40 T antigen transgenes produce tumors and cardiac arrhythmias in mice.
    Science. 1988 Feb 26;239(4843):1029-33 PMID: 2964082
  197. Impaired immune and acute-phase responses in interleukin-6-deficient mice.
    Nature. 1994 Mar 24;368(6469):339-42 PMID: 8127368
  198. Endomitosis and polyploidization of myocardial cells in the periphery of human acute myocardial infarction.
    Cardiovasc Res. 2005 Jul 1;67(1):116-23 PMID: 15949475
  199. Cardiac stem cell and myocyte aging, heart failure, and insulin-like growth factor-1 overexpression.
    Circ Res. 2004 Mar 5;94(4):514-24 PMID: 14726476
  200. Cyclins and cyclin dependent kinases during cardiac development.
    Mol Cells. 1997 Jun 30;7(3):360-6 PMID: 9264023
  201. Tuberous sclerosis: from tubers to mTOR.
    Ann Hum Genet. 2003 Jan;67(Pt 1):87-96 PMID: 12556239
  202. Myocardial regeneration by activation of multipotent cardiac stem cells in ischemic heart failure.
    Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8692-7 PMID: 15932947
  203. The role of c-myc in cell growth.
    Curr Opin Genet Dev. 1993 Feb;3(1):44-9 PMID: 8453273
  204. The foundations of contemporary regeneration research: historical perspectives.
    Monogr Dev Biol. 1992;23:1-27 PMID: 1614425
  205. Spatial and temporal expression patterns of the cyclin-dependent kinase (CDK) inhibitors p27Kip1 and p57Kip2 during mouse development.
    Anat Embryol (Berl). 2001 Feb;203(2):77-87 PMID: 11218061
  206. Local insulin-like growth factor I expression induces physiologic, then pathologic, cardiac hypertrophy in transgenic mice.
    FASEB J. 1999 Nov;13(14):1923-9 PMID: 10544175
  207. Loss of a gp130 cardiac muscle cell survival pathway is a critical event in the onset of heart failure during biomechanical stress.
    Cell. 1999 Apr 16;97(2):189-98 PMID: 10219240
  208. Cardiomyocyte proliferation in mice expressing alpha-cardiac myosin heavy chain-SV40 T-antigen transgenes.
    Am J Physiol. 1992 Jun;262(6 Pt 2):H1867-76 PMID: 1377879
  209. Blastocyst implantation depends on maternal expression of leukaemia inhibitory factor.
    Nature. 1992 Sep 3;359(6390):76-9 PMID: 1522892
  210. Cyclin D1 overexpression promotes cardiomyocyte DNA synthesis and multinucleation in transgenic mice.
    J Clin Invest. 1997 Jun 1;99(11):2644-54 PMID: 9169494
  211. Effects of an Rb mutation in the mouse.
    Nature. 1992 Sep 24;359(6393):295-300 PMID: 1406933
  212. Myocyte growth and cardiac repair.
    J Mol Cell Cardiol. 2002 Feb;34(2):91-105 PMID: 11851350
  213. Regeneration gaps: observations on stem cells and cardiac repair.
    J Am Coll Cardiol. 2006 May 2;47(9):1777-85 PMID: 16682301
  214. DNA flow cytometry of myocardial cell nuclei in paraffin-embedded, human autopsy, cardiac tissue.
    Am J Cardiovasc Pathol. 1990;3(1):55-9 PMID: 2139572
  215. E2F4 is essential for normal erythrocyte maturation and neonatal viability.
    Mol Cell. 2000 Aug;6(2):281-91 PMID: 10983976
  216. The beta-catenin/T-cell factor/lymphocyte enhancer factor signaling pathway is required for normal and stress-induced cardiac hypertrophy.
    Mol Cell Biol. 2006 Jun;26(12):4462-73 PMID: 16738313
  217. The retinoblastoma gene family is differentially expressed during embryogenesis.
    Oncogene. 1997 Apr 17;14(15):1789-97 PMID: 9150384
  218. Signaling mechanisms through gp130: a model of the cytokine system.
    Cytokine Growth Factor Rev. 1997 Dec;8(4):241-52 PMID: 9620640
  219. Cyclin-dependent kinase inhibitor expression in human heart failure. A comparison with fetal development.
    Eur Heart J. 1999 Apr;20(8):604-11 PMID: 10337545
  220. Changes in E2F complexes containing retinoblastoma protein family members and increased cyclin-dependent kinase inhibitor activities during terminal differentiation of cardiomyocytes.
    J Mol Cell Cardiol. 1998 Mar;30(3):563-78 PMID: 9515032
  221. E2F binding is required but not sufficient for repression of B-myb transcription in quiescent fibroblasts.
    Oncogene. 1996 Sep 5;13(5):1073-82 PMID: 8806697
  222. Disappearance of cyclin A correlates with permanent withdrawal of cardiomyocytes from the cell cycle in human and rat hearts.
    J Clin Invest. 1995 May;95(5):2275-80 PMID: 7738192
  223. Nuclear targeting of Akt antagonizes aspects of cardiomyocyte hypertrophy.
    Proc Natl Acad Sci U S A. 2006 Aug 8;103(32):11946-51 PMID: 16882732
  224. Formation of binucleated cardiac myocytes in rat heart: II. Cytoskeletal organisation.
    J Mol Cell Cardiol. 1997 Jun;29(6):1553-65 PMID: 9220341
  225. HIF-1alpha induces cell cycle arrest by functionally counteracting Myc.
    EMBO J. 2004 May 5;23(9):1949-56 PMID: 15071503
  226. Liver regeneration.
    J Hepatol. 2000;32(1 Suppl):19-31 PMID: 10728791
  227. TGF-beta control of cell proliferation.
    J Cell Biochem. 2005 Oct 15;96(3):447-62 PMID: 16088940
  228. Overexpression of insulin-like growth factor-1 in the heart is coupled with myocyte proliferation in transgenic mice.
    Proc Natl Acad Sci U S A. 1996 Aug 6;93(16):8630-5 PMID: 8710922
  229. Scar formation after ischemic myocardial injury in MRL mice.
    Cardiovasc Pathol. 2004 Jul-Aug;13(4):203-6 PMID: 15210135
  230. High hopes for the heart.
    N Engl J Med. 2001 Jun 7;344(23):1785-7 PMID: 11396449
  231. Activation of p38 MAP kinase and JNK but not ERK is required for erythropoietin-induced erythroid differentiation.
    Blood. 1998 Sep 15;92(6):1859-69 PMID: 9731042
  232. Protein kinase cascades in the regulation of cardiac hypertrophy.
    J Clin Invest. 2005 Mar;115(3):527-37 PMID: 15765134
  233. Induction of DNA synthesis and apoptosis in cardiac myocytes by E1A oncoprotein.
    J Cell Biol. 1996 Apr;133(2):325-34 PMID: 8609165
  234. Cloning and characterization of murine p16INK4a and p15INK4b genes.
    Oncogene. 1995 Aug 17;11(4):635-45 PMID: 7651726
  235. Formation of binucleated myocardial cells in the neonatal rat. An index for growth hypertrophy.
    Lab Invest. 1984 May;50(5):571-7 PMID: 6232423
  236. p38 MAP kinases: beyond the stress response.
    Trends Biochem Sci. 2000 Jun;25(6):257-60 PMID: 10838561
  237. p53 activates the mitochondrial death pathway and apoptosis of ventricular myocytes independent of de novo gene transcription.
    J Mol Cell Cardiol. 2001 Aug;33(8):1435-45 PMID: 11448132
  238. Hypertrophic growth in cardiac myocytes is mediated by Myc through a Cyclin D2-dependent pathway.
    EMBO J. 2006 Aug 23;25(16):3869-79 PMID: 16902412
  239. Postnatal isl1+ cardioblasts enter fully differentiated cardiomyocyte lineages.
    Nature. 2005 Feb 10;433(7026):647-53 PMID: 15703750
  240. Analysis of C-MYC function in normal cells via conditional gene-targeted mutation.
    Immunity. 2001 Jan;14(1):45-55 PMID: 11163229
  241. Disruption of the CNTF gene results in motor neuron degeneration.
    Nature. 1993 Sep 2;365(6441):27-32 PMID: 8361533
  242. Altered expression of cell cycle proteins and prolonged duration of cardiac myocyte hyperplasia in p27KIP1 knockout mice.
    Circ Res. 1999 Jul 23;85(2):117-27 PMID: 10417393
  243. Cardiac stem cells possess growth factor-receptor systems that after activation regenerate the infarcted myocardium, improving ventricular function and long-term survival.
    Circ Res. 2005 Sep 30;97(7):663-73 PMID: 16141414
  244. Akt/protein kinase B promotes organ growth in transgenic mice.
    Mol Cell Biol. 2002 Apr;22(8):2799-809 PMID: 11909972
  245. Regulation of cyclins and p34CDC2 expression during terminal differentiation of C2C12 myocytes.
    Biochem Biophys Res Commun. 1995 Jan 5;206(1):82-8 PMID: 7818554
  246. Targeted expression of cyclin D2 results in cardiomyocyte DNA synthesis and infarct regression in transgenic mice.
    Circ Res. 2005 Jan 7;96(1):110-8 PMID: 15576649
  247. Genetic control of cell size.
    Curr Opin Genet Dev. 2000 Oct;10(5):529-35 PMID: 10980431
  248. pRb is required for MEF2-dependent gene expression as well as cell-cycle arrest during skeletal muscle differentiation.
    Curr Biol. 1999 May 6;9(9):449-59 PMID: 10322110
  249. In vivo structure of the human cdc2 promoter: release of a p130-E2F-4 complex from sequences immediately upstream of the transcription initiation site coincides with induction of cdc2 expression.
    Mol Cell Biol. 1995 Dec;15(12):6901-13 PMID: 8524257
  250. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34.
    Science. 1997 Aug 8;277(5327):805-8 PMID: 9242607
  251. CD31- but Not CD31+ cardiac side population cells exhibit functional cardiomyogenic differentiation.
    Circ Res. 2005 Jul 8;97(1):52-61 PMID: 15947249
  252. Sustained cardiomyocyte DNA synthesis in whole embryo cultures lacking the TSC2 gene product.
    Am J Physiol. 1997 Sep;273(3 Pt 2):H1619-27 PMID: 9321857
Article Info
Journal
Physiological reviews
Abbr.
Physiol Rev
ISSN
0031-9333
DOI
10.1152/physrev.00032.2006
Published
2007-04-00
Pages
521-44
Language
English
Region
United States
NLM ID
0231714
PMCID
PMC2708177
Subset
IM
Grants
NHLBI NIH HHS · P01 HL080111 · United States
NHLBI NIH HHS · P01-HL-80111 · United States
NHLBI NIH HHS · R01-HL-70748 · United States
NHLBI NIH HHS · R01 HL070748 · United States
NHLBI NIH HHS · R01 HL070748-03 · United States
External Links
PubMed source DOI: 10.1152/physrev.00032.2006 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2