| Project/Area Number |
17591690
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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 |
Urology
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| Research Institution | Yokohama City University |
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Principal Investigator |
NAKAIGAWA Noboru Yokohama City University, Hospital, associate professor, 附属病院, 準教授 (00237207)
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| Co-Investigator(Kenkyū-buntansha) |
YAO Masahiro Yokohama City University, School of Medicine, associate professor, 医学研究科, 準教授 (00260787)
KISHIDA Takeshi Yokohama City University, Hospital, associate professor, 附属病院, 準教授 (60254166)
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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 |
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2006: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2005: ¥1,700,000 (Direct Cost: ¥1,700,000)
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| Keywords | renal cell carcinoma / MET protein / VHL gene / 分子標的 / 情報伝達系 |
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| Research Abstract |
It is well known that inactivation of VHL gene predisposes for human clear cell renal carcinoma (CCRC). But details about critical roles of VHL inactivation during tumorigenesis are still unknown. MET protein is a tyrosine kinase receptor for hepatocyte growth factor/scatter factor (HGF/SF) to regulate cell growth, cell morphology, and cell motility. We demonstrated that MET protein overexpressed in CCRC cells was phosphorylated without HGF/SF. This constitutive phosphorylation of MET protein in CCRC cells was inhibited by the rescue of exogenous wild-type VHL gene without decrease in expression level of MET protein. Interestingly wild-type VHL gene suppressed the phosphorylation of MET protein only under high cell density conditions. Additionally MET protein activated by the inactivation of VHL gene modified the cell adherence including N-cadherin and □-catenin. When activation of MET protein in CCRC cells was inhibited by the MET inhibitor K252a, the growth of CCRC cells in vitro and the tumorigenesis induced by CCRC cells in nude mice were suppressed. From these results we concluded that inactivation of VHL gene induced constitutive phosphorylation of MET protein and modified intercellular adherence structure to trigger the cell growth released from contact inhibition, finally resulting in tumorigenesis. This is one of the mechanisms of CCRC oncogenesis and MET protein has a potential as a molecular target for novel CCRC therapies.
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