Elucidation of redox regulatory mechanisms by transcription factor network

2018 Fiscal Year Final Research Report

• Project Area: Oxygen biology: a new criterion for integrated understanding of life
• Project/Area Number: 26111010
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Hirosaki University
• Principal Investigator: Itoh Ken 弘前大学, 医学研究科, 教授 (10323289)
• Co-Investigator(Kenkyū-buntansha): 鈴木 隆史 東北大学, 医学系研究科, 講師 (70508308) ; 濱崎 純 東京大学, 大学院薬学系研究科(薬学部), 助教 (80533588)
• Project Period (FY): 2014-07-10 – 2019-03-31
• Keywords: Nrf2 / Keap1 / ミトコンドリア / プロテアソーム / 活性酸素 / 酸素ストレス

Outline of Final Research Achievements

We identified the strong physical interaction between Nrf2 and ATF4, and demonstrated that they cooperatively regulates gene expression of a set of cytoprotective genes. We also showed that GCN1L1 regulates cell cycle and embryonic development in a GCN2-independent manner as well as GCN2-dependent amino acid starvation and UV response. We also demonstrated thata Keap1 senses a variety of stresses by using multiple cysteine residues and consequently, Nrf2 inducers can be classified into at least 5 subclasses. We also identified novel regulators of proteasome and an Nrf1 activator during proteasome inhibition.

Free Research Field

ストレス応答

Academic Significance and Societal Importance of the Research Achievements

酸化ストレス応答やタンパク質生体恒常性維持機構に関わる重要な因子を同定するとともに、生体におけるそれらの役割を明らかにした。これらは、加齢性疾患の病態生理を理解し予防法を検討する上で重要な標的因子になると思われる。また、親電子性物質や活性酸素に対するKeap1のセンシング機構を明らかにした。これらは、細胞の酸化ストレス感知機構に重要な意義を持つ。