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Regulation of DNA damage responses through Sumo modification and its application for radiosensitization

Research Project

Project/Area Number 17K10434
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Radiation science
Research InstitutionThe University of Tokyo

Principal Investigator

Enomoto Atsushi  東京大学, 大学院医学系研究科(医学部), 講師 (20323602)

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: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords放射線 / ハイパーサーミア / タンパク質分解 / STK38 / Calpain / カルパイン / リン酸化 / MAPK / MEKK2 / 温熱増感 / プロテオーム解析 / エックス線 / 温熱処理 / 翻訳後修飾 / SUMO化 / DNA損傷応答 / 放射線増感
Outline of Final Research Achievements

Serine-threonine kinase 38 (STK38) is a member of the protein kinase A (PKA)/PKG/PKC-family and is implicated in the regulation of cell division and cell morphogenesis. Here, we show treatment with heat induced degradation of STK38. The calpain inhibitor calpeptin suppressed heat-induced STK38 cleavage. Moreover, in vitro cleavage assay demonstrate that calpain I directly cleaves STK38 at the proximal N-terminal region. Deletion of the N-terminus region increases its stability against heat. We further demonstrate that a MAPKK kinase (MAP3K), MEKK2 prevents heat-induced cleavage of STK38. MEKK2 knockdown enhanced heat-induced degradation of STK38. We performed in vitro MEKK2 assay and identified a key regulatory phosphorylation site in STK38 by MEKK2. Experiments with phosphorylation-defective mutant demonstrate that phosphorylation of Ser 91 is important for STK38 stability, as it is susceptible to attack by the calpain degradation pathway unless this residue is phosphorylated.

Academic Significance and Societal Importance of the Research Achievements

本研究では温熱処理により細胞内においてタンパク質リン酸化酵素の一種であるSTK38がタンパク質分解酵素カルパインによって分解されることを明らかにした。生命科学研究の進展により、温熱に対する細胞応答の分子メカニズムが少しずつ明らかになってきている8, 9)。温熱耐性や抗腫瘍効果をもたらす因子・マーカーの同定が進むことによって、温熱療法と同等以上の効果を生み出す創薬への道も開ける。また放射線や抗がん剤などとの併用を行う上で、温熱標的因子や誘導因子の性質・挙動を把握しておくことは治療スケジュールの計画に重要な指針を与えるであろう。

Report

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

    (14 results)

All 2020 2019 2018 2017

All Journal Article (5 results) (of which Peer Reviewed: 4 results,  Open Access: 3 results) Presentation (9 results)

  • [Journal Article] Prevention of calpain-dependent degradation of STK38 by MEKK2-mediated phosphorylation.2019

    • Author(s)
      A. Enomoto, T. Fukasawa, H. Tsumoto, M. Karube, K. Nakagawa, A. Yoshizaki, S. Sato, Y. Miura, K. Miyagawa.
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1 Pages: 1038-1038

    • DOI

      10.1038/s41598-019-52435-8

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] ストレス応答キナーゼSTK38タンパク質の温熱感受性機構2019

    • Author(s)
      榎本 敦
    • Journal Title

      放射線生物研究

      Volume: 54 Pages: 150-157

    • NAID

      40021971282

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 温熱による抗腫瘍効果の真の標的解明と臨床・創薬への応用2018

    • Author(s)
      榎本 敦
    • Journal Title

      日本健康開発雑誌

      Volume: 39 Pages: 30-36

    • NAID

      130007734318

    • Related Report
      2018 Research-status Report
  • [Journal Article] A chemical modulator of p53 transactivation that acts as a radioprotective agonist.2018

    • Author(s)
      Akinori Morita, Ippei Takahashi, Megumi Sasatani, Shin Aoki, Bing Wang, Shinya Ariyasu, Kaoru Tanaka, Tetsuji Yamaguchi, Akiko Sawa, Yurie Nishi, Tatsuro Teraoka, Shohei Ujita, Yosuke Kawate, Chihiro Yanagawa, Keiji Tanimoto, Atsushi Enomoto, Mitsuru Nenoi, Kenji Kamiya, Yasushi Nagata, Yoshio Hosoi and Toshiya Inaba
    • Journal Title

      Molecular Cancer Therapeutics

      Volume: 17 Issue: 2 Pages: 432-442

    • DOI

      10.1158/1535-7163.mct-16-0554

    • NAID

      120006552353

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Checkpoint kinase 2 is dispensable for regulation of the p53 response but is required for G2/M arrest and cell survival in cells with p53 defects under heat stress2017

    • Author(s)
      Furusawa Yukihiro、Yamanouchi Yuka、Iizumi Takashi、Zhao Qing-Li、Mitsuhashi Yohei、Morita Akinori、Enomoto Atushi、Tabuchi Yoshiaki、Kondo Takashi
    • Journal Title

      Apoptosis

      Volume: 22 Issue: 10 Pages: 1225-1234

    • DOI

      10.1007/s10495-017-1402-2

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 温熱によるCa2+/カルパインを介した放射線増感メカニズム2020

    • Author(s)
      榎本敦、深澤毅倫、宮川清
    • Organizer
      第20回癌治療増感シンポジウム
    • Related Report
      2019 Annual Research Report
  • [Presentation] ストレス応答キナーゼSTK38お安定性と放射線増感への応用2019

    • Author(s)
      榎本敦、深澤毅倫、宮川清
    • Organizer
      日本放射線腫瘍学会第57回生物部会
    • Related Report
      2019 Annual Research Report
  • [Presentation] ストレス応答キナーゼSTK38の安定性制御メカニズム2019

    • Author(s)
      榎本敦、深澤毅倫、宮川清
    • Organizer
      日本放射線影響学会第62回大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] STK38の安定性制御メカニズム2019

    • Author(s)
      榎本敦、深澤毅倫、宮川清
    • Organizer
      日本分子生物学会第42回年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] ストレス応答キナーゼSTK38の安定性と放射線増感への応用2018

    • Author(s)
      榎本 敦、深澤 毅倫、宮川 清
    • Organizer
      日本放射線腫瘍学会生物部会
    • Related Report
      2018 Research-status Report
  • [Presentation] ストレス応答キナーゼSTK38の安定性と放射線増感への応用2018

    • Author(s)
      榎本 敦、深澤 毅倫、宮川 清
    • Organizer
      日本放射線影響学会
    • Related Report
      2018 Research-status Report
  • [Presentation] ストレス応答キナーゼSTK38の安定性と放射線増感への応用2018

    • Author(s)
      榎本敦、深澤毅倫、宮川清
    • Organizer
      国際癌治療増感研究協会・第20回癌治療増感シンポジウム
    • Related Report
      2017 Research-status Report
  • [Presentation] STK38/NDR1の安定性制御メカニズム2017

    • Author(s)
      榎本敦、深澤毅倫、宮川清
    • Organizer
      日本分子生物学会・第40回日本分子生物学会年会
    • Related Report
      2017 Research-status Report
  • [Presentation] ストレス応答キナーゼSTK38の安定性と放射線増感への応用2017

    • Author(s)
      榎本敦、深澤毅倫、宮川清
    • Organizer
      日本放射線影響学会・第60回大会
    • Related Report
      2017 Research-status Report

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

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