Study on molecular mechanism of p62-Keap1-Nrf2 system

2018 Fiscal Year Final Research Report

• Project/Area Number: 16H05137
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Niigata University
• Principal Investigator: Ichimura Yoshinobu 新潟大学, 医歯学系, 准教授 (80400993)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 選択的オートファジー / p62-Keap1-Nrf2経路 / p62

Outline of Final Research Achievements

We have previously reported that phosphorylation of p62 at Ser349 markedly increases p62’s binding affinity for Keap1, an adaptor of the Cul3-ubiquitin E3 ligase complex responsible for degrading Nrf2, and induces expression of cytoprotective Nrf2 targets (p62-Keap1-Nrf2 axis). Further, we have demonstrated that the S349-phosphorylated p62 causes rearrangement of glucose and glutamine metabolism through persistent activation of Nrf2, which provides HCC cells with both tolerance to anti-cancer drugs and proliferation potency. However, the molecular mechanisms regulating the p62-Keap1-Nrf2 axis are not yet fully understood. In this study, we performed high-content screening with human whole siRNA library. Further, we established derivatives of K67, inhibitor for the Keap1-phosphorylated p62 interaction, and developed fluorescent K67-derivertive.

Free Research Field

生化学

Academic Significance and Societal Importance of the Research Achievements

p62-Keap1-Nrf2経路は、p62のリン酸化を介して転写因子Nrf2が活性化される経路である。重要なことに、本経路は肝がん細胞株や肝がん患者組織では恒常的に活性化されており、がん細胞の増殖に有利な代謝リプログラミングや薬剤耐性を介してがんの悪性化に寄与している。すなわち、p62-Keap1-Nrf2経路を制御することが、がんの有効な治療手段となる。しかしながら、p62-Keap1-Nrf2経路の制御機構については十分に理解されていない。本研究課題ではp62-Keap1-Nrf2経路の制御に関わる新規な低分子化合物を同定し、そのメカニズムを明らかにした。さらに制御因子の探索を進めた。