Down-regulation of p27Kip1 promotes cell proliferation of rat neonatal cardiomyocytes induced by nuclear expression of cyclin D1 and CDK4

Evidence for impaired Skp2-dependent degradation of p27 in terminal differentiation

Mimi Tamamori-Adachi, Kentaro Hayashida, Kiyoshi Nobori, Chie Omizu, Kazuhiko Yamada, Naoya Sakamoto, Takumi Kamura, Keiichi Fukuda, Satoshi Ogawa, Keiichi I. Nakayama, Shigetaka Kitajima

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Mammalian cardiomyocytes lose their capacity to proliferate during terminal differentiation. We have previously reported that the expression of nuclear localization signal-tagged cyclin D1 (D1NLS) and its partner cyclin-dependent kinase 4 (CDK4) induces proliferation of rat neonatal cardiomyocytes. Here we show that the D1NLS/CDK4 cells, after their entry into the cell cycle, accumulated cyclin-dependent kinase inhibitor p27 in the nuclei and decreased the cyclin-dependent kinase 2 (CDK2) activity, leading to early cell cycle arrest. Biochemical analysis demonstrated that Skp2-dependent p27 ubiquitylation was remarkably suppressed in cardiomyocytes, whereas Skp2, a component of Skp1-Cullin-F-box protein ubiquitin ligase, was more actively ubiquitylated compared with proliferating rat fibroblasts. Specific degradation of p27 by co-expressing Skp2 or p27 small interfering RNA caused an increase of CDK2 activity and overrode the limited cell cycle. These data altogether indicate that the impaired Skp2-dependent p27 degradation is causally related to the loss of proliferation in cardiomyocytes. This provides a novel insight in understanding the molecular mechanism by which mammalian cardiomyocytes cease to proliferate during terminal differentiation.

Original languageEnglish
Pages (from-to)50429-50436
Number of pages8
JournalJournal of Biological Chemistry
Volume279
Issue number48
DOIs
Publication statusPublished - 2004 Nov 26

Fingerprint

Cyclin-Dependent Kinase 4
Cyclin D1
Cell proliferation
Cardiac Myocytes
Cyclin-Dependent Kinase 2
Rats
Down-Regulation
Cells
Cell Proliferation
Degradation
SKP Cullin F-Box Protein Ligases
Cyclin-Dependent Kinase Inhibitor p27
Fibroblasts
Ligases
Ubiquitin
Cell Cycle
Small Interfering RNA
Nuclear Localization Signals
Ubiquitination
Cell Cycle Checkpoints

ASJC Scopus subject areas

  • Biochemistry

Cite this

Down-regulation of p27Kip1 promotes cell proliferation of rat neonatal cardiomyocytes induced by nuclear expression of cyclin D1 and CDK4 : Evidence for impaired Skp2-dependent degradation of p27 in terminal differentiation. / Tamamori-Adachi, Mimi; Hayashida, Kentaro; Nobori, Kiyoshi; Omizu, Chie; Yamada, Kazuhiko; Sakamoto, Naoya; Kamura, Takumi; Fukuda, Keiichi; Ogawa, Satoshi; Nakayama, Keiichi I.; Kitajima, Shigetaka.

In: Journal of Biological Chemistry, Vol. 279, No. 48, 26.11.2004, p. 50429-50436.

Research output: Contribution to journalArticle

Tamamori-Adachi, Mimi ; Hayashida, Kentaro ; Nobori, Kiyoshi ; Omizu, Chie ; Yamada, Kazuhiko ; Sakamoto, Naoya ; Kamura, Takumi ; Fukuda, Keiichi ; Ogawa, Satoshi ; Nakayama, Keiichi I. ; Kitajima, Shigetaka. / Down-regulation of p27Kip1 promotes cell proliferation of rat neonatal cardiomyocytes induced by nuclear expression of cyclin D1 and CDK4 : Evidence for impaired Skp2-dependent degradation of p27 in terminal differentiation. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 48. pp. 50429-50436.
@article{e1105ae25cc640ea9e833c156163e0fd,
title = "Down-regulation of p27Kip1 promotes cell proliferation of rat neonatal cardiomyocytes induced by nuclear expression of cyclin D1 and CDK4: Evidence for impaired Skp2-dependent degradation of p27 in terminal differentiation",
abstract = "Mammalian cardiomyocytes lose their capacity to proliferate during terminal differentiation. We have previously reported that the expression of nuclear localization signal-tagged cyclin D1 (D1NLS) and its partner cyclin-dependent kinase 4 (CDK4) induces proliferation of rat neonatal cardiomyocytes. Here we show that the D1NLS/CDK4 cells, after their entry into the cell cycle, accumulated cyclin-dependent kinase inhibitor p27 in the nuclei and decreased the cyclin-dependent kinase 2 (CDK2) activity, leading to early cell cycle arrest. Biochemical analysis demonstrated that Skp2-dependent p27 ubiquitylation was remarkably suppressed in cardiomyocytes, whereas Skp2, a component of Skp1-Cullin-F-box protein ubiquitin ligase, was more actively ubiquitylated compared with proliferating rat fibroblasts. Specific degradation of p27 by co-expressing Skp2 or p27 small interfering RNA caused an increase of CDK2 activity and overrode the limited cell cycle. These data altogether indicate that the impaired Skp2-dependent p27 degradation is causally related to the loss of proliferation in cardiomyocytes. This provides a novel insight in understanding the molecular mechanism by which mammalian cardiomyocytes cease to proliferate during terminal differentiation.",
author = "Mimi Tamamori-Adachi and Kentaro Hayashida and Kiyoshi Nobori and Chie Omizu and Kazuhiko Yamada and Naoya Sakamoto and Takumi Kamura and Keiichi Fukuda and Satoshi Ogawa and Nakayama, {Keiichi I.} and Shigetaka Kitajima",
year = "2004",
month = "11",
day = "26",
doi = "10.1074/jbc.M403084200",
language = "English",
volume = "279",
pages = "50429--50436",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "48",

}

TY - JOUR

T1 - Down-regulation of p27Kip1 promotes cell proliferation of rat neonatal cardiomyocytes induced by nuclear expression of cyclin D1 and CDK4

T2 - Evidence for impaired Skp2-dependent degradation of p27 in terminal differentiation

AU - Tamamori-Adachi, Mimi

AU - Hayashida, Kentaro

AU - Nobori, Kiyoshi

AU - Omizu, Chie

AU - Yamada, Kazuhiko

AU - Sakamoto, Naoya

AU - Kamura, Takumi

AU - Fukuda, Keiichi

AU - Ogawa, Satoshi

AU - Nakayama, Keiichi I.

AU - Kitajima, Shigetaka

PY - 2004/11/26

Y1 - 2004/11/26

N2 - Mammalian cardiomyocytes lose their capacity to proliferate during terminal differentiation. We have previously reported that the expression of nuclear localization signal-tagged cyclin D1 (D1NLS) and its partner cyclin-dependent kinase 4 (CDK4) induces proliferation of rat neonatal cardiomyocytes. Here we show that the D1NLS/CDK4 cells, after their entry into the cell cycle, accumulated cyclin-dependent kinase inhibitor p27 in the nuclei and decreased the cyclin-dependent kinase 2 (CDK2) activity, leading to early cell cycle arrest. Biochemical analysis demonstrated that Skp2-dependent p27 ubiquitylation was remarkably suppressed in cardiomyocytes, whereas Skp2, a component of Skp1-Cullin-F-box protein ubiquitin ligase, was more actively ubiquitylated compared with proliferating rat fibroblasts. Specific degradation of p27 by co-expressing Skp2 or p27 small interfering RNA caused an increase of CDK2 activity and overrode the limited cell cycle. These data altogether indicate that the impaired Skp2-dependent p27 degradation is causally related to the loss of proliferation in cardiomyocytes. This provides a novel insight in understanding the molecular mechanism by which mammalian cardiomyocytes cease to proliferate during terminal differentiation.

AB - Mammalian cardiomyocytes lose their capacity to proliferate during terminal differentiation. We have previously reported that the expression of nuclear localization signal-tagged cyclin D1 (D1NLS) and its partner cyclin-dependent kinase 4 (CDK4) induces proliferation of rat neonatal cardiomyocytes. Here we show that the D1NLS/CDK4 cells, after their entry into the cell cycle, accumulated cyclin-dependent kinase inhibitor p27 in the nuclei and decreased the cyclin-dependent kinase 2 (CDK2) activity, leading to early cell cycle arrest. Biochemical analysis demonstrated that Skp2-dependent p27 ubiquitylation was remarkably suppressed in cardiomyocytes, whereas Skp2, a component of Skp1-Cullin-F-box protein ubiquitin ligase, was more actively ubiquitylated compared with proliferating rat fibroblasts. Specific degradation of p27 by co-expressing Skp2 or p27 small interfering RNA caused an increase of CDK2 activity and overrode the limited cell cycle. These data altogether indicate that the impaired Skp2-dependent p27 degradation is causally related to the loss of proliferation in cardiomyocytes. This provides a novel insight in understanding the molecular mechanism by which mammalian cardiomyocytes cease to proliferate during terminal differentiation.

UR - http://www.scopus.com/inward/record.url?scp=9644281053&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=9644281053&partnerID=8YFLogxK

U2 - 10.1074/jbc.M403084200

DO - 10.1074/jbc.M403084200

M3 - Article

VL - 279

SP - 50429

EP - 50436

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 48

ER -