Degradation of the CDK inhibitor p27^<Kip1> by a novel ubiquitin ligase.
| Project/Area Number |
17590243
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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 |
General medical chemistry
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| Research Institution | Hamamatsu University School of Medicine |
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Principal Investigator |
UCHIDA Chiharu Hamamatu University, School of Medicine, Research Associate, 医学部, 助手 (60223567)
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| Co-Investigator(Kenkyū-buntansha) |
KITAGAWA Masatoshi Hamamatu University, School of Medicine, Professor, 医学部, 教授 (50294971)
HATTORI Takayuki Hamamatu University, School of Medicine, Post doctoral fellow (COE), 医学部, COE研究員 (50377751)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | p27kip1 / Ubiquitin / Proteasome / Degradation / Cell cycle / p27<kip1> |
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| Research Abstract |
Cell cycle progression is controlled by cyclin-dependent kinases (CDKs). The CDK activities are negatively regulated by CDK inhibitor proteins (CKIs). In the quiescent and early G1 phase, p27^<Kip1>, one of the Cip/Kip-type CKIs, exists in abundance in the cell nucleus to suppress cell cycle progression. p27^<Kip1> is degraded in late G1 phase by the ubiquitin-proteasome pathway, allowing cells to enter S phase. In this study, we identified p27NBP1 as a p27^<Kip1>-interacting protein. p27NBP1 physically interacted with p27^<Kip1> and directly ubiquitinated p27^<Kip1> in an intact RING finger domain-dependent manner. Since we isolated p27NBP1 as a protein that interacts with the amino-terminal portion of p27^<Kip1> containing Ser10, we next examined whether interaction between these two proteins was affected by Ser10 phosphorylation status. In spite of the substitution of Ser10, p27^<Kip1> mutants associated with p27NBP1 to an extent similar to that of wild-type p27^<Kip1>. This result suggested that p27NBP1 interacts with p27^<Kip1> regardless of the status of Ser10 phosphorylation. Ablation of endogenous p27NBP1 by small interfering RNA increased the steady-state level of p27^<Kip1> and decelerated p27^<Kip1> turnover. p27^<Kip1> was decreased in synchronization with accumulation of p27NBP1 in late G1 phase. Furthermore, depletion of p27NBP1 resulted in inhibition of cell cycle progression from G1 to S phase in a p53-independent manner. Overall, the results indicate that p27NBP1 acts as a negative regulator of p27^<Kip1> function by promoting ubiquitin-dependent proteasomal degradation.
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Report
(3 results)
Research Products
(22 results)
