| Project/Area Number |
13460148
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Applied molecular and cellular biology
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| Research Institution | Tohoku University |
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Principal Investigator |
UCHIDA Takafumi Tohoku University, Center for Interdisciplinary Research, Associate Professor, 学際科学国際高等研究センター, 助教授 (80312239)
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| Co-Investigator(Kenkyū-buntansha) |
FUKUMOTO Manabu Tohoku University, Institute of Development, Aging and Cancer, Professor, 加齢医学研究所, 教授 (60156809)
UCHIDA Chiyoko Ibaraki University, Health Center, Associate Professor, 保健管理センター, 助教授 (80312776)
FUJIMORI Fumihiro Tokyo Science University, Engineering, Assistant Professor, 基礎工学部, 助手 (50318226)
竹林 勇二 東北大学, 加齢医学研究所, 助手 (70321982)
八木 淳二 東京女子医科大学, 講師 (70182300)
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| Project Period (FY) |
2001 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥12,700,000 (Direct Cost: ¥12,700,000)
Fiscal Year 2003: ¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2002: ¥4,900,000 (Direct Cost: ¥4,900,000)
Fiscal Year 2001: ¥4,300,000 (Direct Cost: ¥4,300,000)
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| Keywords | Pint / Knock Out Mouse / Cancer / Neurodenerative Disease / p53 / Tau / myc / Par14 / アルツハイマー病 / 神経原繊維変化 / がん遺伝子 / ノックアウトマウス / インヒビター / リン酸化 / 細胞周期 / アポトーシス / フォールディング / ペプチジルプロリルイソメラーゼ / cyclinD / 酵母 |
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| Research Abstract |
The phosphorylation of proteins is a vital biological signal in cells, critical for processes such as signal transduction, cell cycle progression, and apoptosis. It is well documented that the addition of a phosphate group can cause a protein to assume a different biological role from its unphosphorylated form. However, what is not understood is the structural basis for the observed functional changes as a result of phosphorylation. Peptidyl prolyl cis-trans isomerase (PPIase) catalyzes the cis-trans isomerization of prolyl peptide bonds, and PPIase activity is required for the assembly, folding, and transport of cellular proteins. Pin1 is a PPIase from the pavilion family chat may be particularly important for cell signaling because, in addition to its PPIase domain, it has a WW domain at its N terminus that recognizes and interacts with phosphoserine (pSer) or phosphothreonine (pThr)-proline motifs in several proteins. Specifically, Pin1 binds to pSer/pThr-Pro sequences and isomerizes pSer/pThr-Pro bonds, altering the protein conformation in a phosphorylation-dependent manner and/or promoting protein dephosphorylation. This strongly supports a role for Pin1 as an integral component of the change in function of phosphorylated proteins. In mice, a knockout of the Pin1 gene resulted in viable offspring, albeit with detectable phenotypes, such as such as retinal atrophy, impaired mammary epithelial expansion during pregnancy, infertile and age-dependent neurodegeneration. The analysis of the cells prepared from Pin1-KO mice showed that Pin1 regulates the level and the activities of p53 positively and Pin1 controls c-myc degradation. We also screened chemical library and identified a series of inhibitors. They were used to show that Pin1 is important for cell cycle progression.
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