title: Two inhibitory systems and CKIs regulate cell cycle exit of mammalian cardiomyocytes after birth.
abstract: Mammalian cardiomyocytes actively proliferate during embryonic stages, following which they exit their cell cycle after birth, and the exit is maintained. Previously, we showed that two inhibitory systems (the G1-phase inhibitory system: repression of cyclin D1 expression; the M-phase inhibitory system: inhibition of CDK1 activation) maintain the cell cycle exit of mouse adult cardiomyocytes. We also showed that two CDK inhibitors (CKIs), p21(Cip1) and p27(Kip1), regulate the cell cycle exit in a portion of postnatal cardiomyocytes. It remains unknown whether the two inhibitory systems are involved in the cell cycle exit of postnatal cardiomyocytes and whether p21(Cip1) and p27(Kip1) also inhibit entry to M-phase. Here, we showed that more than 40% of cardiomyocytes entered an additional cell cycle by induction of cyclin D1 expression at postnatal stages, but M-phase entry was inhibited in the majority of cardiomyocytes. Marked cell cycle progression and endoreplication were observed in cardiomyocytes of p21(Cip1) knockout mice at 4 weeks of age. In addition, tri- and tetranucleated cardiomyocytes increased significantly in p21(Cip1) knockout mice. These data showed that the G1-phase inhibitory system and two CKIs (p21(Cip1) and p27(Kip1)) inhibit entry to an additional cell cycle in postnatal cardiomyocytes, and that the M-phase inhibitory system and p21(Cip1) inhibit M-phase entry of cardiomyocytes which have entered the additional cell cycle.
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: Hitomi
authors.initials: H
authors.lastname: Okayama
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: Yuki
authors.initials: Y
authors.lastname: Amemiya
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; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000096:biosynthesis; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000166:cytology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*
chemical_list: C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D047428:Protein Kinase Inhibitors; D019938:Cyclin D1; D018844:Cyclin-Dependent Kinases
keywords: CDK inhibitor; CDK1; Cardiomyocyte; Cell cycle exit; Cyclin D1; Karyokinesis