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Identification of the tareget molecule for GSK-3 activator DIF towards clinical usage

Research Project

Project/Area Number 17K08598
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field General pharmacology
Research InstitutionUniversity of Occupational and Environmental Health, Japan

Principal Investigator

Takahashi Fumi  産業医科大学, 医学部, 教授 (50274436)

Co-Investigator(Kenkyū-buntansha) 笹栗 俊之  九州大学, 医学研究院, 教授 (30261209)
Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
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)
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
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.

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。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (8 results)

All 2020 2019 2017

All Journal Article (4 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 4 results) Presentation (4 results)

  • [Journal Article] Differentiation‐inducing factor‐1 suppresses cyclin D1‐induced cell proliferation of MCF‐7 breast cancer cells by inhibiting S6K‐mediated signal transducer and activator of transcription 3 synthesis2019

    • Author(s)
      Tetsuo Fumi、Arioka Masaki、Miura Koichi、Kai Misato、Kubo Momoko、Igawa Kazunobu、Tomooka Katsuhiko、Takahashi‐Yanaga Fumi、Nishimura Fusanori、Sasaguri Toshiyuki
    • Journal Title

      Cancer Science

      Volume: 110 Issue: 12 Pages: 3761-3772

    • DOI

      10.1111/cas.14204

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 2,5-Dimethylcelecoxib prevents isoprenaline-induced cardiomyocyte hypertrophy and cardiac fibroblast activation by inhibiting Akt-mediated GSK-3 phosphorylation.2019

    • Author(s)
      Morishige S, Takahashi-Yanaga F, Ishikane S, Arioka M, Igawa K, Kuroo A, Tomooka K, Shiose A, Sasaguri T.
    • Journal Title

      Biochemical Pharmacology

      Volume: 168 Pages: 82-90

    • DOI

      10.1016/j.bcp.2019.06.018

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Glycogen synthase kinase-3 inhibitor as a multi-targeting anti-rheumatoid drug.2019

    • Author(s)
      M. Arioka and F Takahashi-Yanaga
    • Journal Title

      Biochemical Pharmacology

      Volume: 印刷中 Pages: 207-213

    • DOI

      10.1016/j.bcp.2019.02.020

    • Related Report
      2019 Annual Research Report 2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Anti-tumor effects of differentiation-inducing factor-1 in malignant melanoma: GSK-3-mediated inhibition of cell proliferation and GSK-3-independent suppression of cell migration and invasion.2017

    • Author(s)
      Arioka M, Takahashi-Yanaga F, Kubo M, Igawa K, Sasaguri T.
    • Journal Title

      Biochemical Pharmacology

      Volume: 138 Pages: 31-48

    • DOI

      10.1016/j.bcp.2017.05.004

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] Differentiation-inducing factor-1 suppresses breast cancer cell proliferation by reducing STAT3-mediated cyclin D1 expression2020

    • Author(s)
      哲翁 ふみ, 有岡 将基, 高橋 富美, 西村 英紀, 笹栗 俊之
    • Organizer
      第93回日本薬理学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Differentiation-inducing factor-1によるトリプルネガティブ乳癌の抑制機序2019

    • Author(s)
      哲翁ふみ, 有岡将基, 高橋富美, 西村英紀, 笹栗俊之
    • Organizer
      第72回日本薬理学会西南部会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Differentiation-Inducing Factor はYAPを介してHippoシグナル伝達経路に影響を及ぼす2019

    • Author(s)
      高橋 富美,石兼 真、豊平 由美子
    • Organizer
      第92回 日本薬理学会年会
    • Related Report
      2018 Research-status Report
  • [Presentation] Anti-tumor effect of DIF-1 in malignant melanoma2017

    • Author(s)
      高橋 富美、有岡 将基、久保 桃子、笹栗 俊之
    • Organizer
      第76回日本癌学会
    • Related Report
      2017 Research-status Report

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Published: 2017-04-28   Modified: 2021-02-19  

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