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

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K19027
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: General medical chemistry
• Research Institution: Tohoku University
• Principal Investigator: Baird Liam 東北大学, 医学系研究科, 助教 (90724914)
• Research Collaborator: Yamamoto Masayuki ; Suzuki Takafumi
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: Keap1-Nrf2

Outline of Final Research Achievements

The Keap1-Nrf2 pathway is the body’s principle inducible defense against electrophilic and oxidative stress, and as such plays an important role in cellular homeostasis and human health. In order to study the molecular mechanism of Keap1-dependent Nrf2 regulation, I used a new mouse model of Nrf2 activation, in which the weak binding DLG motif has been mutated into an additional ETGE motif, which binds tightly to Keap1. Analysis of this mouse revealed no change in the oxidative stress response, suggesting that the release of the DLG motif is not required for Nrf2 activation in response to electrophilic inducers. This approach was complemented by in vitro studies of the Keap1-Cul3 complex, which revealed that the majority of Nrf2 inducers do not impact the composition of the Keap1-Cul3 complex.

Free Research Field

Molecular Biology

Academic Significance and Societal Importance of the Research Achievements

Nrf2活性化による疾患治療効果を最大限にするために、詳細なNrf2の誘導機構の理解が不可欠である。本研究の成果は酸化ストレスによるNrf2活性化の分子機構において新しい知見を与えた。今後のNrf2活性化メカニズムの研究およびNrf2誘導剤の開発において有益な情報を得ることができた。