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

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K10434
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Radiation science
• 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)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 放射線 / ハイパーサーミア / タンパク質分解 / STK38 / Calpain

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.

Free Research Field

放射線生物学

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。