• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Identification of non-canonical degradation pathway of HIF-1 alpha promoted by de-ubiqutinating enzyme inhibitor.

Research Project

Project/Area Number 16K07114
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Tumor biology
Research InstitutionKyoto University

Principal Investigator

Hattori Akira  京都大学, 薬学研究科, 准教授 (50300893)

Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywordsユビキチン / 脱ユビキチン化酵素活性 / 低酸素誘導因子 / プロテアソーム / タンパク質分解 / 低酸素応答 / HIF-1 / 脱ユビキチン化酵素 / p38MAPキナーゼ / anisomycin
Outline of Final Research Achievements

We found that inhibition of de-ubiquitinating enzymes (DUB), which release ubiquitin (Ub) moieties from Ub chain, promoted a degradation of hypoxia-inducible factor(HIF)-1α through a unidentified proteasome-independent pathway. We revealed that WP1130, a DUB inhibitor, activated the p38 MAP kinase pathway and anisomycin, a p38 MAP kinase activator, promoted the degradation of HIF-1α which accumulated by the proteasome inhibition. These results suggested that WP1130 activates non-canonical HIF-1α degradation pathway via p38 MAP kinase pathway. We constructed a series of C-terminal deletion mutants and demonstrated that a region between residues 375 and 600 of HIF-1α is essential for the induction of non-canonical degradation pathway. Study employing various protease inhibitors including ALLN, a calpain-I inhibitor, suggested that calpain-I inhibitor ALLN-sensitive protease is involved in the WP1130-induced degradation of HIF-1α accumulated by proteasome-inhibition,

Academic Significance and Societal Importance of the Research Achievements

がん治療におけるHIF-1機能制御の有効性は既に広く認識されている。本研究の結果、脱ユビキチン化酵素の阻害によって誘導される新しいHIF-1α分解経路が、がん悪性化に対する新しい制御点として機能しうることが明らかとなった。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (8 results)

All 2019 2018 2017 2016

All Journal Article (3 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 3 results) Presentation (5 results)

  • [Journal Article] Acute-phase protein-like properties of endoplasmic reticulum aminopeptidase 1.2019

    • Author(s)
      Goto Y, Nakamura TJ, Ogawa K, Hattori A, Tsujimoto M.
    • Journal Title

      J Biochem.

      Volume: 165 Issue: 2 Pages: 159-165

    • DOI

      10.1093/jb/mvy090

    • NAID

      40021809947

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Factors Regulating Human Extravillous Trophoblast Invasion: Chemokine-peptidase and CD9-integrin Systems2018

    • Author(s)
      Fujiwara Hiroshi、Matsumoto Hisanori、Sato Yukiyasu、Horie Akihito、Ono Masanori、Nakamura Mitsuhiro、Mizumoto Yasunari、Kagami Kyosuke、Fujiwara Tomoko、Hattori Akira、Maida Yoshiko、Daikoku Takiko、Imakawa Kazuhiko、Araki Yoshihiko
    • Journal Title

      Current Pharmaceutical Biotechnology

      Volume: 19 Issue: 10 Pages: 764-770

    • DOI

      10.2174/1389201019666181029164906

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] CD9 suppresses human extravillous trophoblast invasion2016

    • Author(s)
      Matsumoto H, Sato Y, Horie A, Suginami K, Tani H, Hattori A, Araki Y, Kagami K, Konishi I, Fujiwara H
    • Journal Title

      Placenta

      Volume: 47 Pages: 105-112

    • DOI

      10.1016/j.placenta.2016.09.014

    • Related Report
      2016 Research-status Report
    • Peer Reviewed
  • [Presentation] 酵素反応速度論的解析を用いた脱ユビキチン化酵素USP47の C末端領域の機能解析2018

    • Author(s)
      福岡啓太、服部 明、掛谷秀昭
    • Organizer
      第91回日本生化学会大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Calpain7の細胞内局在の解析2018

    • Author(s)
      松原拓真、服部 明、掛谷秀昭
    • Organizer
      第91回日本生化学会大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 脱ユビキチン化酵素USP47のC末端ホモロジー領域はそのポリユビキチン鎖認識機構に重要である2017

    • Author(s)
      福岡啓太
    • Organizer
      2017生命科学系学会合同年次大会
    • Related Report
      2017 Research-status Report
  • [Presentation] 脱ユビキチン化酵素阻害によるHIF-1発現レベルの制御2016

    • Author(s)
      吹上遼介
    • Organizer
      第89回日本生化学大会
    • Place of Presentation
      仙台国際センター他(宮城県)
    • Year and Date
      2016-09-25
    • Related Report
      2016 Research-status Report
  • [Presentation] 脱ユビキチン化酵素USP47のポリユビキチン鎖消化機構の解明2016

    • Author(s)
      福岡啓太
    • Organizer
      第89回日本生化学大会
    • Place of Presentation
      仙台国際センター他(宮城県)
    • Year and Date
      2016-09-25
    • Related Report
      2016 Research-status Report

URL: 

Published: 2016-04-21   Modified: 2020-03-30  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi