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 Nakayama, Shigetaka Kitajima

Research output: Contribution to journalArticle

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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 - Nov 26 2004

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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

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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; 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 ; 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.
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