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Elucidating the molecular mechanism by which tumor suppressor Notch1 is inactivated by xylosyl-extension

Research Project

Project/Area Number 17H06743
Research Category

Grant-in-Aid for Research Activity Start-up

Allocation TypeSingle-year Grants
Research Field Functional biochemistry
Research InstitutionNagoya University

Principal Investigator

Takeuchi Hideyuki  名古屋大学, 医学系研究科, 准教授 (80361608)

Research Collaborator URATA yusuke  
Project Period (FY) 2017-08-25 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
KeywordsO-グルコース糖鎖 / Notch1 / Notch シグナル / 糖転移酵素 / キシロース / 腫瘍抑制因子 / Notchシグナル / 扁平上皮癌 / 糖鎖 / O-グルコース
Outline of Final Research Achievements

The PI hypothesized that carcinogenesis and elevated proliferation of AML and squamous carcinoma are caused by aberrantly increased xylosylation of O-glucose glycans on Notch1. Here, as an initial step of our long-term research, we examined the structures of O-glucose glycans on Notch1 and whether it is possible to manipulate the extent of xylosyl-extension of O-glucose glycans on Notch1 by genetically engineering the genes that encode the xylosyltransferases. We accomplished the comprehensive analysis of O-glucose glycans on Notch1 produced in cultured cell lines. Furthermore, as expected, knocking out of XXYLT1 resulted in loss of the addition of the terminal xylose residues at a non-reducing end of O-glucose glycans on Notch1, and knocking out both GXYLT1 and GXYLT2 resulted in loss of xylosyl-extension of O-glucose glycans on Notch1.

Academic Significance and Societal Importance of the Research Achievements

O-グルコース糖鎖キシロース伸長は、Notch1の小胞体内品質管理と、細胞表面におけるリガンド結合に寄与している可能性がある。Notch1 上の O-グルコース糖鎖修飾プロファイルは、これまでに報告がなかったが、本研究により、初めてそれが明らかとなった。現段階では培養細胞由来の解析結果であり、今後、生体試料でも同様の解析をしていく必要がある。そして、それらの情報を活用することにより、Notch1 受容体を介したシグナル伝達機構の制御に関する分子メカニズムの解明と、Notch シグナルの異常に起因する病態の診断および治療法の開発に資することが期待される。

Report

(3 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Annual Research Report
  • Research Products

    (6 results)

All 2019 2018

All Journal Article (1 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 1 results) Presentation (5 results) (of which Int'l Joint Research: 2 results,  Invited: 2 results)

  • [Journal Article] Protein O-glucosylation: another essential role of glucose in biology2019

    • Author(s)
      Hongjun Yu and Hideyuki Takeuchi
    • Journal Title

      Current Opinion in Structural Biology

      Volume: 56 Pages: 64-71

    • DOI

      10.1016/j.sbi.2018.12.001

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] Significant roles of O-glucose glycans in mammalian Notch trafficking and signaling2018

    • Author(s)
      Hideyuki Takeuchi
    • Organizer
      Annual Meeting of Society for Glycobiology
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 新しい 2 種類のタンパク質 O-グルコース転移酵素 (POGLUT) は POGLUT1 とは異なり Notch リガンド結合表面のアミノ酸を修飾する2018

    • Author(s)
      竹内英之
    • Organizer
      第 91 回日本生化学会大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] O-結合型糖鎖は上皮増殖因子様リピートの安定性を変化させることにより Notch のトラフィッキングを制御する2018

    • Author(s)
      竹内英之
    • Organizer
      第 41 回日本分子生物学会年会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Exploring the significance of xylosyl-extension of O-glucose glycans on EGF repeats for Notch signaling in mammals2018

    • Author(s)
      Wataru Saiki, Yusuke Urata, Yuya Senoo, Yohei Tsukamoto, Chenyu Ma, Tetsuya Okajima, and Hideyuki Takeuchi
    • Organizer
      Annual Meeting of Society for Glycobiology
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] O-グルコース糖鎖のキシロシル化の Notch シグナルにおける役割の解析2018

    • Author(s)
      浦田悠輔、竹内英之、岡島徹也
    • Organizer
      第 91 回日本生化学会大会
    • Related Report
      2018 Annual Research Report

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Published: 2017-08-25   Modified: 2020-03-30  

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