2004 Fiscal Year Final Research Report Summary
Study of cell cycle mechanism for heart regeneration
| Project/Area Number |
15590728
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
ADACHI Mimi Tokyo Medical and Dental University, Medical Research Institute, assistant professor, 難治疾患研究所, 助手 (10323693)
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| Project Period (FY) |
2003 – 2004
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| Keywords | cardiomyocyte / p27 / Skp2 / cell cycle progression / cyclin D1 / CDK4 / nuclear localization signal / ユビキチン化 |
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| Research 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 the 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 to proliferating rat fibroblasts. Specific degradation of p27 by co-expressing Skp2 or p27siRNA 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.
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Research Products
(9 results)
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[Journal Article] Down-regulation of p27^<Kip1> promotes cell proliferation of rat neonatal cardiomyocytes induced by nuclear expression of cyclinD1 and CDK4 : Evidence for impaired Skp2-dependent degradation of p27 in terminal differentiation.2004
Author(s)
Tamamori-Adachi M., Hayashida K, Nobori K, Omizu C, Yamada K, Sakamoto N, Kamura T, Fukuda K, Ogawa S, Nakayama KI, Kitajima S
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Journal Title
J.Biol.Chem. 279
Pages: 50429-50436
Description
「研究成果報告書概要(欧文)」より
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