title: CDK inhibitors, p21(Cip1) and p27(Kip1), participate in cell cycle exit of mammalian cardiomyocytes.
abstract: Mammalian cardiomyocytes actively proliferate during embryonic stages, following which cardiomyocytes exit their cell cycle after birth. The irreversible cell cycle exit inhibits cardiac regeneration by the proliferation of pre-existing cardiomyocytes. Exactly how the cell cycle exit occurs remains largely unknown. Previously, we showed that cyclin E- and cyclin A-CDK activities are inhibited before the CDKs levels decrease in postnatal stages. This result suggests that factors such as CDK inhibitors (CKIs) inhibit CDK activities, and contribute to the cell cycle exit. In the present study, we focused on a Cip/Kip family, which can inhibit cyclin E- and cyclin A-CDK activities. Expression of p21(Cip1) and p27(Kip1) but not p57(Kip2) showed a peak around postnatal day 5, when cyclin E- and cyclin A-CDK activities start to decrease. p21(Cip1) and p27(Kip1) bound to cyclin E, cyclin A and CDK2 at postnatal stages. Cell cycle distribution patterns of postnatal cardiomyocytes in p21(Cip1) and p27(Kip1) knockout mice showed failure in the cell cycle exit at G1-phase, and endoreplication. These results indicate that p21(Cip1) and p27(Kip) play important roles in the cell cycle exit of postnatal cardiomyocytes.
authors.affiliation: School of Life Sciences, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Tane
authors.affiliation: School of Life Sciences, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan.
authors.forename: Aiko
authors.initials: A
authors.lastname: Ikenishi
authors.affiliation: School of Life Sciences, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Okayama
authors.affiliation: School of Life Sciences, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Iwamoto
authors.affiliation: Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Keiichi I
authors.initials: KI
authors.lastname: Nakayama
authors.affiliation: School of Life Sciences, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan. Electronic address: takeuchi@med.tottori-u.ac.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Takeuchi
mesh_terms: D000818:Animals; D002453:Cell Cycle; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D005786:Gene Expression Regulation; D008322:Mammals / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism*
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27
keywords: CDK; CDK inhibitor; CKI; CM; Cardiomyocyte; Cell cycle exit; KO; Mouse; cardiomyocyte; cyclin dependent kinase; cyclin dependent kinase inhibitor; knockout