Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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Molecular Basis of the KEAP1-NRF2 Signaling Pathway

  • Takafumi Suzuki (Department of Medical Biochemistry, Tohoku University Graduate School of Medicine) ;
  • Jun Takahashi (Department of Medical Biochemistry, Tohoku University Graduate School of Medicine) ;
  • Masayuki Yamamoto (Department of Medical Biochemistry, Tohoku University Graduate School of Medicine)
  • Received : 2023.02.05
  • Accepted : 2023.03.04
  • Published : 2023.03.31
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Abstract

Transcription factor NRF2 (NF-E2-related factor 2) is a master regulator of cellular responses against environmental stresses. NRF2 induces expression of detoxification and antioxidant enzymes and suppresses inductions of pro-inflammatory cytokine genes. KEAP1 (Kelch-like ECH-associated protein 1) is an adaptor subunit of CULLIN 3 (CUL3)-based E3 ubiquitin ligase. KEAP1 regulates the activity of NRF2 and acts as a sensor for oxidative and electrophilic stresses. NRF2 has been found to be activated in many types of cancers with poor prognosis. Therapeutic strategies to control NRF2-overeactivated cancers have been considered not only by targeting cancer cells with NRF2 inhibitors or NRF2 synthetic lethal chemicals, but also by targeting host defense with NRF2 inducers. Understanding precise molecular mechanisms how the KEAP1-NRF2 system senses and regulates the cellular response is critical to overcome intractable NRF2-activated cancers.

Keywords

Acknowledgement

This work was supported in part by MEXT/JSPS KAKENHI (19H05649 to M.Y. and 22K06876 to T.S.), the Takeda Science Foundation (to T.S.), the Suzuken Memorial Foundation (to T.S.), the Mochida Memorial Foundation for Medical and Pharmaceutical Research (to T.S.), the Foundation for Promotion of Cancer Research (to T.S.), the Gonryo Medical Foundation (to T.S.), the Life Science Foundation of Japan (to T.S.), and Research Support Project for Life Science and Drug Discovery (Basis for Supporting Innovative Drug Discovery and Life Science Research [BINDS]) from AMED (JP22ama121038 to M.Y.).

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