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Dissecting the molecular mechanism of Wnt receptor ubiquitination by RNF43.

Research Project

Project/Area Number 19K07633
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 50010:Tumor biology-related
Research InstitutionHokkaido University

Principal Investigator

Tsukiyama Tadasuke  北海道大学, 医学研究院, 助教 (20399819)

Project Period (FY) 2019-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
KeywordsRNF43 / Wnt / p53 / tumorigenesis / ubiquitin / 発がん / リン酸化 / 多段階発がん / シグナルクロストーク / ユビキチン化 / 大腸がん / Fzd / がん治療 / multistep tumorigenesis / crosstalk / Ras / FGF / がん / 組織修復
Outline of Research at the Start

申請者らは、幹細胞特異的ユビキチンリガーゼであるRNF43がp53経路を抑制すること、Wnt受容体のFzdを分解すること、がん抑制遺伝子として機能していること、その遺伝子変異によってがん遺伝子へと転換することを報告してきた。しかしRNF43は比較的最近発見された分子であり、その機能にはまだ不明な点が多い。本研究では、RNF43によるp53経路とWntシグナルを調節する分子メカニズムを詳細に解明し、また解明したメカニズムを応用して組織修復と関連した新たながん治療法の確立をめざす。

Outline of Final Research Achievements

In this research project, we focused on elucidating the regulatory mechanism of the Wnt receptor degradation via the functional switch of RNF43 by its phosphorylation, and the molecular mechanism by which RNF43 gene mutation is involved in carcinogenesis.
On these projects, we have reported that the phospho-switch of RNF43 roles the direction of Wnt signaling to the activation or suppression, and that missense mutations in this switch abolish the function of RNF43 and invert it from a tumor suppressor to an oncogene. These results were published in Nature Communications. Also, we reported a review explaining the outline of Wnt receptor regulation and oncogenesis/onco-therapy in BioEssay. In addition, the results in our research were introduced in the media in several TV news programs and a special program for cancer research/treatment. Therefore, we think that our research was evaluated as well-contributed to the society domestically and internationally.

Academic Significance and Societal Importance of the Research Achievements

大腸がんは死者数の上位3位以内を占め、また国民の約1割が生涯において大腸がんと診断されることから、日本の医療に大きなインパクトを与えている疾患といえる。また大腸がんは、左側に発生する比較的予後の良いタイプと、右側に発生する予後の悪いタイプに分けられる。本研究で焦点を当てたユビキチン化酵素RNF43の遺伝子変異は左側では殆ど見られないが、右側のがんではこの左側での遺伝子変異とは相互排他的に高頻度に観察される。しかし、その発がんにおける分子的詳細は明らかになっていなかった。本研究にて得られた結果は、予後の悪い右側大腸がんの発症機序を理解した上で、今後の治療方針を決定する上での大きな知見となった。

Report

(5 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (28 results)

All 2023 2022 2021 2020 2019 Other

All Int'l Joint Research (10 results) Journal Article (4 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 4 results,  Open Access: 3 results) Presentation (11 results) (of which Int'l Joint Research: 3 results,  Invited: 4 results) Remarks (3 results)

  • [Int'l Joint Research] オーストリアバイオテクノロジー研究所(オーストリア)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] 基礎科学研究院(韓国)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] ケンブリッジ大学(英国)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] University of Turin(イタリア)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] オーストリア・バイオテクノロジー研究所(オーストリア)

    • Related Report
      2021 Research-status Report
  • [Int'l Joint Research] University of Turin(イタリア)

    • Related Report
      2021 Research-status Report
  • [Int'l Joint Research] オーストリアバイオテクノロジー研究所(オーストリア)

    • Related Report
      2020 Research-status Report
  • [Int'l Joint Research] ケンブリッジ大学(英国)

    • Related Report
      2020 Research-status Report
  • [Int'l Joint Research] IMBA(オーストリア)

    • Related Report
      2019 Research-status Report
  • [Int'l Joint Research] ケンブリッジ大学(英国)

    • Related Report
      2019 Research-status Report
  • [Journal Article] Wnt/β-Catenin Signaling Stabilizes Hemidesmosomes in Keratinocytes2022

    • Author(s)
      Kosumi Hideyuki、Watanabe Mika、Shinkuma Satoru、Nohara Takuma、Fujimura Yu、Tsukiyama Tadasuke、Donati Giacomo、Iwata Hiroaki、Nakamura Hideki、Ujiie Hideyuki、Natsuga Ken
    • Journal Title

      Journal of Investigative Dermatology

      Volume: 142 Issue: 6 Pages: 1576-1586.e2

    • DOI

      10.1016/j.jid.2021.10.018

    • Related Report
      2022 Annual Research Report 2021 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Post‐translational Wnt receptor regulation: Is the fog slowly clearing?2021

    • Author(s)
      Tsukiyama Tadasuke、Koo Bon‐Kyoung、Hatakeyama Shigetsugu
    • Journal Title

      BioEssays

      Volume: 43 Issue: 4 Pages: 2000297-2000297

    • DOI

      10.1002/bies.202000297

    • Related Report
      2021 Research-status Report 2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A phospho-switch controls RNF43-mediated degradation of Wnt receptors to suppress tumorigenesis2020

    • Author(s)
      Tsukiyama Tadasuke、Zou Juqi、Kim Jihoon、Ogamino Shohei、Shino Yuki、Masuda Takamasa、Merenda Alessandra、Matsumoto Masaki、Fujioka Yoichiro、Hirose Tomonori、Terai Sayuri、Takahashi Hidehisa、Ishitani Tohru、Nakayama Keiichi I.、Ohba Yusuke、Koo Bon-Kyoung、Hatakeyama Shigetsugu
    • Journal Title

      Nature Communications

      Volume: 11 Issue: 1 Pages: 1-16

    • DOI

      10.1038/s41467-020-18257-3

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The role of Mediator and Little Elongation Complex in transcription termination2020

    • Author(s)
      Takahashi H, Ranjan A, Chen S, Suzuki H, Shibata M, Hirose T, Hirose H, Sasaki K, Abe R, Chen K, He Y, Zhang Y, Takigawa I, Tsukiyama T, Watanabe M, Fujii S, Iida M, Yamamoto J, Yamaguchi Y, Suzuki Y, Matsumoto M, Nakayama KI, Washburn P, Saraf A, Florens L, Sato S, Tomomori-Sato C, Conaway RC, Conaway JW, Hatakeyama S
    • Journal Title

      Nature Communications

      Volume: 11 Issue: 1 Pages: 1-20

    • DOI

      10.1038/s41467-020-14849-1

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] 多段階発がんにおけるRNF43遺伝子変異の意義2023

    • Author(s)
      築山忠維
    • Organizer
      北海道がん若手研究者交流会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] Wnt receptor regulation and maintaining homeostasis2023

    • Author(s)
      Tadasuke Tsukiyama
    • Organizer
      CGE International Seminar Series 2023
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Wnt受容体調節の破綻が多段階発がん過程で果たす複雑な役割2022

    • Author(s)
      築山忠維
    • Organizer
      第59回日本生化学会北海道支部例会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] Wnt 受容体調節の破綻が多段階発がん過程で果たす複雑な役割2022

    • Author(s)
      築山忠維・畠山鎮次
    • Organizer
      第81回日本癌学会学術総会
    • Related Report
      2022 Annual Research Report
  • [Presentation] A role of RNF43 other than Wnt receptor regulation in oncogenesis (poster)2022

    • Author(s)
      Tadasuke Tsukiyama
    • Organizer
      Wnt 2022
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] A role of RNF43 other than Wnt receptor regulation in oncogenesis (oral)2022

    • Author(s)
      Tadasuke Tsukiyama
    • Organizer
      Wnt 2022
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Wnt受容体の発現調節異常と発がん機構の解明2021

    • Author(s)
      築山忠維、石谷太、高橋秀尚、松本雅記、大場雄介、中山敬一、Koo Bonkyoung、畠山鎮次
    • Organizer
      第94回日本生化学会大会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] Wnt receptor regulation2021

    • Author(s)
      築山忠維
    • Organizer
      Wnt研究会2021
    • Related Report
      2020 Research-status Report
  • [Presentation] 単一遺伝子変異による多段階発がんの起動と完成2020

    • Author(s)
      築山忠維・石谷太・畠山鎮次
    • Organizer
      第79回日本癌学会学術総会
    • Related Report
      2020 Research-status Report
  • [Presentation] 幹細胞特異的ユビキチンリガーゼRNF43の遺伝子変異による多段階発がんステップの起動と完成2019

    • Author(s)
      築山忠維・石谷太・畠山鎮次
    • Organizer
      第78回日本癌学会学術総会
    • Related Report
      2019 Research-status Report
  • [Presentation] RNF43の遺伝子変異は多段階発がんステップにおいてWntとp53経路の変異を代償する2019

    • Author(s)
      築山忠維・篠裕輝・寺井小百合・高橋秀尚・BK Koo・石谷太・畠山鎮次
    • Organizer
      第43回日本分子生物学会年会
    • Related Report
      2019 Research-status Report
  • [Remarks] 北海道大学大学院医学研究院医化学教室

    • URL

      https://hokudai-ikagaku.jp

    • Related Report
      2021 Research-status Report 2019 Research-status Report
  • [Remarks] 大腸がん発症のスイッチを発見~一度壊れた遺伝子にがん抑制効果を回復させる~

    • URL

      https://www.hokudai.ac.jp/news/2020/09/post-723.html

    • Related Report
      2020 Research-status Report
  • [Remarks] Molecular basis underlying colorectal cancer ~

    • URL

      https://www.global.hokudai.ac.jp/blog/molecular-basis-underlying-colorectal-cancer-revealed/

    • Related Report
      2020 Research-status Report

URL: 

Published: 2019-04-18   Modified: 2024-01-30  

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