title: Repression of cyclin D1 expression is necessary for the maintenance of cell cycle exit in adult mammalian cardiomyocytes.
abstract: The hearts of neonatal mice and adult zebrafish can regenerate after injury through proliferation of preexisting cardiomyocytes. However, adult mammals are not capable of cardiac regeneration because almost all cardiomyocytes exit their cell cycle. Exactly how the cell cycle exit is maintained and how many adult cardiomyocytes have the potential to reenter the cell cycle are unknown. The expression and activation levels of main cyclin-cyclin-dependent kinase (CDK) complexes are extremely low or undetectable at adult stages. The nuclear DNA content of almost all cardiomyocytes is 2C, indicating the cell cycle exit from G1-phase. Here, we induced expression of cyclin D1, which regulates the progression of G1-phase, only in differentiated cardiomyocytes of adult mice. In these cardiomyocytes, S-phase marker-positive cardiomyocytes and the expression of main cyclins and CDKs increased remarkably, although cyclin B1-CDK1 activation was inhibited in an ATM/ATR-independent manner. The phosphorylation pattern of CDK1 and expression pattern of Cdc25 subtypes suggested that a deficiency in the increase in Cdc25 (a and -b), which is required for M-phase entry, inhibited the cyclin B1-CDK1 activation. Finally, analysis of cell cycle distribution patterns showed that >40% of adult mouse cardiomyocytes reentered the cell cycle by the induction of cyclin D1. The cell cycle of these binucleated cardiomyocytes was arrested before M-phase, and many mononucleated cardiomyocytes entered endoreplication. These data indicate that silencing the cyclin D1 expression is necessary for the maintenance of the cell cycle exit and suggest a mechanism that involves inhibition of M-phase entry.
authors.affiliation: From the School of Life Sciences, Faculty of Medicine.
authors.forename: Shoji
authors.initials: S
authors.lastname: Tane
authors.affiliation: Mitsubishi Kagaku Institute of Life Sciences, Machida 194-8511, Japan, and.
authors.forename: Misae
authors.initials: M
authors.lastname: Kubota
authors.affiliation: From the School of Life Sciences, Faculty of Medicine.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Okayama
authors.affiliation: From the School of Life Sciences, Faculty of Medicine.
authors.forename: Aiko
authors.initials: A
authors.lastname: Ikenishi
authors.affiliation: From the School of Life Sciences, Faculty of Medicine.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yoshitome
authors.affiliation: From the School of Life Sciences, Faculty of Medicine.
authors.forename: Noriko
authors.initials: N
authors.lastname: Iwamoto
authors.affiliation: From the School of Life Sciences, Faculty of Medicine.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Satoh
authors.affiliation: Mitsubishi Kagaku Institute of Life Sciences, Machida 194-8511, Japan, and.
authors.forename: Aoi
authors.initials: A
authors.lastname: Kusakabe
authors.affiliation: Mitsubishi Kagaku Institute of Life Sciences, Machida 194-8511, Japan, and.
authors.forename: Satoko
authors.initials: S
authors.lastname: Ogawa
authors.affiliation: From the School of Life Sciences, Faculty of Medicine.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Kanai
authors.affiliation: Cincinnati Children's Hospital Medical Center, University of Cincinnati, Howard Hughes Medical Institute, Cincinnati, Ohio 45229.
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
authors.affiliation: Division of Laboratory Animal Science, Research Center for Bioscience and Technology, Tottori University, Yonago 683-8503, Japan.
authors.forename: Kazuomi
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Division of Laboratory Animal Science, Research Center for Bioscience and Technology, Tottori University, Yonago 683-8503, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Ohbayashi
authors.affiliation: From the School of Life Sciences, Faculty of Medicine, Mitsubishi Kagaku Institute of Life Sciences, Machida 194-8511, Japan, and takeuchi@med.tottori-u.ac.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Takeuchi
mesh_terms: D000818:Animals; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle; D056744:Cyclin B1 / Q000235:genetics / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D006321:Heart / Q000254:growth & development*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism*
chemical_list: D056744:Cyclin B1; D019938:Cyclin D1; D016203:CDC2 Protein Kinase
keywords: Cardiac Muscle; Cell Cycle; Cyclin D1; Gene Silencing; Regeneration