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Role of dysregulation of zinc-dependent proteostasis signaling in zinc deficiency

Research Project

Project/Area Number 18K06957
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 49010:Pathological biochemistry-related
Research InstitutionJuntendo University (2020-2022)
Kobe University (2018-2019)

Principal Investigator

Edamatsu Hironori  順天堂大学, 医学部, 准教授 (70335438)

Project Period (FY) 2018-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
KeywordsRAS / がん / 脆弱性 / 小胞体ストレス / 亜鉛恒常性 / トランスクリプトーム / 細胞死 / タンパク質恒常性 / RAS遺伝子 / 亜鉛 / 細胞内シグナル伝達 / Ras / JNK / p38 / UPR / MAPキナーゼ / IRE1 / シャペロン / ストレス応答 / ras / シグナル伝達 / 亜鉛生物学 / マーカー遺伝子
Outline of Final Research Achievements

Expression of constitutively active Hras (HrasG12V) under zinc-deficient conditions led to the activation of caspase-3 and stress-activated MAPKs (JNK and p38MAPK). The induction of these stress responses depended on the activation of ERK, which is downstream of Ras. HrasG12V expression induced endoplasmic reticulum (ER) stress, which was further exacerbated by zinc deficiency to activate JNK and p38MAPK through IRE1. In addition, HrasG12V expression upregulated the expression of a subset of zinc-binding proteins, which appears to dysregulate zinc homeostasis and proteostasis and to confer vulnerability to zinc deficiency.

Academic Significance and Societal Importance of the Research Achievements

亜鉛欠乏下でのRasシグナルの恒常的活性化が引き起こす細胞死の誘導機構の解析を目指した本研究は、細胞の生存における亜鉛恒常性の重要性を見出した。さらに、Rasシグナル伝達の異常な亢進が亜鉛結合タンパク質の生合成を亢進させ、その結果、亜鉛恒常性を破綻させる可能性を指摘することができた。今後、本研究で得られた成果をさらに発展させることで、がん細胞の新たな脆弱性の発見に繋がると思われる。

Report

(6 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (3 results)

All 2022 2019 2018

All Journal Article (1 results) (of which Peer Reviewed: 1 results) Presentation (2 results)

  • [Journal Article] Zinc ions negatively regulate proapoptotic signaling in cells expressing oncogenic mutant Ras2022

    • Author(s)
      Hironori Edamatsu
    • Journal Title

      BioMetals

      Volume: 35 Issue: 2 Pages: 349-362

    • DOI

      10.1007/s10534-022-00376-7

    • Related Report
      2022 Annual Research Report 2021 Research-status Report
    • Peer Reviewed
  • [Presentation] rasシグナルによる亜鉛依存的ストレス応答に関連した遺伝子の網羅的発現解析2019

    • Author(s)
      枝松 裕紀
    • Organizer
      第18回日本亜鉛栄養治療研究会
    • Related Report
      2018 Research-status Report
  • [Presentation] 活性型変異体Hras発現細胞における亜鉛依存的遺伝子発現の解析2018

    • Author(s)
      枝松 裕紀
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Research-status Report

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Published: 2018-04-23   Modified: 2024-01-30  

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