An investigation into the mechanism regulating the oxidative stress-dependent activation of the Keap1-Nrf2 pathway

2017 年度 実施状況報告書

• 研究課題/領域番号: 16K19027
• 研究機関: 東北大学
• 研究代表者: Baird Liam 東北大学, 医学系研究科, 助教 (90724914)
• 研究期間 (年度): 2016-04-01 – 2019-03-31
• キーワード: Keap1-Nrf2

研究実績の概要

The main aim of this project was to develop a new mouse model in which to study the mechanism of Keap1-dependent regulation of the transcription factor Nrf2. To achieve this aim, we developed a new Nrf2 Dual-ETGE transgenic mouse in which to study the oxidative stress response in vivo. Through analysis of these mice, we found that the replacement of the DLG motif in Nrf2 with an additional ETGE motif did not inhibit the chemical induced activation of Nrf2. In addition, we assayed the stoichiometry of the Nrf2-Keap1-Cul3 complex, and found that this complex is not dissociated by chemical inducers of Nrf2. This suggests that the Nrf2-Keap1-Cul3 complex is inactivated by inducers, but that this activation is not caused by the dissociation of the Keap1 complex upon chemical activation of Nrf2.

現在までの達成度 (区分)

2: おおむね順調に進展している

理由

As we have already made and analysed the Dual-ETGE transgenic mice, we are now able to take the next step in the project by generating structural data to study the mechanism of Keap1 inactivation by chemical inducers.

今後の研究の推進方策

Over the final year of the project, we will continue to develop and utilize new structural biology techniques in order to gain a deep and fresh insight into the molecular mechanism of the Keap1-dependent regulation of Nrf2.

次年度使用額が生じた理由

The money used last year was for research materials and to attend a conference. For the next fiscal year, the money will be used for research materials.

研究成果

• [雑誌論文] Hyperactivation of Nrf2 in early tubular development induces nephrogenic diabetes insipidus (2017)
  • 著者名/発表者名: Suzuki T, Seki S, Hiramoto K, Naganuma E, Kobayashi EH, Yamaoka A, Baird L, Takahashi N, Sato H, Yamamoto M.
  • 雑誌名: Nature Communications 巻: 8 ページ: 1,13
  • DOI: 10.1038/ncomms14577
  • 査読あり / オープンアクセス / 国際共著