Abstract
The inability of heart muscle to regenerate by replication of existing cardiomyocytes has engendered considerable interest in identifying developmental or other stimuli capable of sustaining the proliferative capacity of immature cardiomyocytes or stimulating division of postmitotic cardiomyocytes. Here, we demonstrate that reactivation of Notch signaling causes embryonic stem cell-derived and neonatal ventricular cardiomyocytes to enter the cell cycle. The proliferative response of neonatal ventricular cardiomyocytes declines as they mature, such that late activation of Notch triggers the DNA damage checkpoint and G2/M interphase arrest. Notch induces recombination signal-binding protein 1 for Jkappa (RBP-Jkappa)-dependent expression of cyclin D1 but, unlike other inducers, also shifts its subcellular distribution from the cytosol to the nucleus. Nuclear localization of cyclin D1 is independent of RBP-Jkappa. Thus, the influence of Notch on nucleocytoplasmic localization of cyclin D1 is an unanticipated property of the Notch intracellular domain that is likely to regulate the cell cycle in multiple contexts, including tumorigenesis as well as cardiogenesis.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus
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Animals
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Animals, Newborn
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Apoptosis / drug effects
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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CDC2 Protein Kinase / metabolism
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Caffeine / pharmacology
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Cell Cycle / drug effects
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Cell Cycle / physiology*
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Cell Nucleus / metabolism
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Cell Proliferation
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Cells, Cultured
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Cyclin D1 / metabolism
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Immunoglobulin J Recombination Signal Sequence-Binding Protein / genetics
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Immunoglobulin J Recombination Signal Sequence-Binding Protein / metabolism
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Mice
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Models, Biological
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Myocytes, Cardiac / cytology
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Myocytes, Cardiac / metabolism*
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Phosphorylation
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Rats
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Rats, Sprague-Dawley
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Receptor, Notch2 / physiology
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Receptors, Notch / physiology*
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Retinoblastoma Protein / metabolism
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Time Factors
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Transcription Factor HES-1
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Transfection
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Hes1 protein, rat
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Homeodomain Proteins
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Immunoglobulin J Recombination Signal Sequence-Binding Protein
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Receptor, Notch2
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Receptors, Notch
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Retinoblastoma Protein
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Transcription Factor HES-1
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Cyclin D1
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Caffeine
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Glycogen Synthase Kinase 3 beta
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CDC2 Protein Kinase
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Glycogen Synthase Kinase 3