Regulation of DNA damage responses through Sumo modification and its application for radiosensitization
Project/Area Number |
17K10434
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Research Field |
Radiation science
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Research Institution | The 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)
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Project Period (FY) |
2017-04-01 – 2020-03-31
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Project Status |
Completed (Fiscal Year 2019)
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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)
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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.
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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。
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Report
(4 results)
Research Products
(14 results)
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[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
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Journal Title
Molecular Cancer Therapeutics
Volume: 17
Issue: 2
Pages: 432-442
DOI
NAID
Related Report
Peer Reviewed / Open Access
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