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      The KEAP1-NRF2 System: a Thiol-Based Sensor-Effector Apparatus for Maintaining Redox Homeostasis.

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          Abstract

          The Kelch-like ECH-associated protein 1-NF-E2-related factor 2 (KEAP1-NRF2) system forms the major node of cellular and organismal defense against oxidative and electrophilic stresses of both exogenous and endogenous origins. KEAP1 acts as a cysteine thiol-rich sensor of redox insults, whereas NRF2 is a transcription factor that robustly transduces chemical signals to regulate a battery of cytoprotective genes. KEAP1 represses NRF2 activity under quiescent conditions, whereas NRF2 is liberated from KEAP1-mediated repression on exposure to stresses. The rapid inducibility of a response based on a derepression mechanism is an important feature of the KEAP1-NRF2 system. Recent studies have unveiled the complexities of the functional contributions of the KEAP1-NRF2 system and defined its broader involvement in biological processes, including cell proliferation and differentiation, as well as cytoprotection. In this review, we describe historical milestones in the initial characterization of the KEAP1-NRF2 system and provide a comprehensive overview of the molecular mechanisms governing the functions of KEAP1 and NRF2, as well as their roles in physiology and pathology. We also refer to the clinical significance of the KEAP1-NRF2 system as an important prophylactic and therapeutic target for various diseases, particularly aging-related disorders. We believe that controlled harnessing of the KEAP1-NRF2 system is a key to healthy aging and well-being in humans.

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          Author and article information

          Journal
          Physiol. Rev.
          Physiological reviews
          American Physiological Society
          1522-1210
          0031-9333
          Jul 01 2018
          : 98
          : 3
          Affiliations
          [1 ] Department of Medical Biochemistry, Graduate School of Medicine, Tohoku University , Sendai , Japan ; Department of Pharmacology & Chemical Biology, University of Pittsburgh , Pittsburgh, Pennsylvania ; and Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University , Sendai , Japan.
          Article
          10.1152/physrev.00023.2017
          29717933
          ea28a875-5a48-4a3d-a8b6-b2f2256d057b
          History

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