| Project/Area Number |
17K08598
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
General pharmacology
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| Research Institution | University of Occupational and Environmental Health, Japan |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
笹栗 俊之 九州大学, 医学研究院, 教授 (30261209)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | 抗がん薬 / 細胞内シグナル調節 / 分子標的薬 / 抗腫瘍薬 / GSK-3 / YAP / G1期特異的 |
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| Outline of Final Research Achievements |
Differentiation-inducing factors (DIFs), first identified in Dictyostelium discoideum, also affect mammalian cells. We reported that DIF-1 and DIF-3 inhibited mammalian cell proliferation by activation of glycogen synthase kinase-3(GSK-3). However, the target molecule(s) of DIFs to activate GSK-3 are not identified yet. Therefore, we tried to clarify the target molecule(s) of DIF using affinity chromatography with DIF-1-tethered resin and found that 14-3-3ζcould be a candidate protein. We performed quartz crystal microbalance assay. DIFs were revealed to directly bind to 14-3-3ζ. We further confirmed binding of DIF 14-3-3ζby thermal shift assay and found that DIF affect 14-3-3ζprotein stability. As 14-3-3ζis known to associate with Yes-associated protein (YAP), we analyzed the effect of 14-3-3ζknock down on YAP. We found that DIF-1 significantly reduced phosphorylation level of YAP, thereby activating YAP to translocate to nucleus in HeLa cells.
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| Academic Significance and Societal Importance of the Research Achievements |
14-3-3ζはがん細胞の転移や浸潤に大きな役割を果たすHippoシグナル経路の活性調節因子であるYes-associated protein (YAP)と結合することにより、この転写因子の核内移行を制御し、Hippoシグナル経路活性調節に関与することが知られている。DIFによる抗腫瘍効果の検討を行う過程で、がん細胞の転移や浸潤はGSK-3に非依存的に起こる可能性を見出していたので、DIFの作用機序解明にあたって、新たにHippoシグナル経路を加えることができたのは、大きな収穫であった。
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