Notch activates cell cycle reentry and progression in quiescent cardiomyocytes.
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.
Campa
Víctor M
VM
Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
Gutiérrez-Lanza
Raquel
R
Cerignoli
Fabio
F
Díaz-Trelles
Ramón
R
Nelson
Brandon
B
Tsuji
Toshiya
T
Barcova
Maria
M
Jiang
Wei
W
Mercola
Mark
M
D021581:Active Transport, Cell Nucleus; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002110:Caffeine / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D051883:Receptor, Notch2 / Q000502:physiology; D051880:Receptors, Notch / Q000502:physiology*; D016160:Retinoblastoma Protein / Q000378:metabolism; D013997:Time Factors; D000072056:Transcription Factor HES-1; D014162:Transfection
D051792:Basic Helix-Loop-Helix Proteins; D016203:CDC2 Protein Kinase; D002110:Caffeine; D019938:Cyclin D1; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D018398:Homeodomain Proteins; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D051883:Receptor, Notch2; D051880:Receptors, Notch; D016160:Retinoblastoma Protein; D000072056:Transcription Factor HES-1; C489735:Hes1 protein, rat