REVIEW ARTICLE The cytoprotective role of the Keap1–Nrf2 pathway Liam Baird • Albena T. Dinkova-Kostova Received: 6 December 2010 / Accepted: 8 February 2011 / Published online: 2 March 2011 Ó Springer-Verlag 2011 Abstract An elaborate network of highly inducible pro- teins protects aerobic cells against the cumulative damag- ing effects of reactive oxygen intermediates and toxic electrophiles, which are the major causes of neoplastic and chronic degenerative diseases. These cytoprotective pro- teins share common transcriptional regulation, through the Keap1–Nrf2 pathway, which can be activated by various exogenous and endogenous small molecules (inducers). Inducers chemically react with critical cysteine residues of the sensor protein Keap1, leading to stabilisation and nuclear translocation of transcription factor Nrf2, and ultimately to coordinate enhanced expression of genes coding for cytoprotective proteins. In addition, inducers inhibit pro-inflammatory responses, and there is a linear correlation spanning more than six orders of magnitude of concentrations between inducer and anti-inflammatory activity. Genetic deletion of transcription factor Nrf2 ren- ders cells and animals much more sensitive to the dam- aging effects of electrophiles, oxidants and inflammatory agents in comparison with their wild-type counterparts. Conversely, activation of the Keap1–Nrf2 pathway allows survival and adaptation under various conditions of stress and has protective effects in many animal models. Cross- talks with other signalling pathways broadens the role of the Keap1–Nrf2 pathway in determining the fate of the cell, impacting fundamental biological processes such as proliferation, apoptosis, angiogenesis and metastasis. Keywords Keap1 Á Nrf2 Á Cytoprotective enzymes Á Phase 2 inducer Introduction In the late 1980s, Paul Talalay and his colleagues predicted the existence of a protein endowed with highly reactive cysteine residue(s) that serves as the sensor for small- molecule inducers of cytoprotective enzymes, such as NAD(P)H:quinone acceptor oxidoreductase 1 (NQO1) and glutathione S-transferases (GSTs). In a seminal study (Talalay et al. 1988) aiming to obtain mechanistic insights into the perplexing question of how numerous structurally diverse small molecules induce these proteins, a common chemical signature was identified, leading the investigators to conclude: ‘‘…it is gratifying that the capacity of an extraordinary variety of seemingly unrelated anticarcino- gens to induce protective enzymes can be attributed to the presence, or acquisition by metabolism, of a simple and hitherto unrecognized chemical property: that of a Michael reaction acceptor.’’ Following the discovery of Keap1 by Masayuki Yamamoto and his colleagues (Itoh et al. 1999) as the repressor of transcription factor Nrf2 that regulates the expression of these cytoprotective genes, the first question was: ‘‘Does Keap1 have any (reactive) cysteine residues?’’ In the ensuing years, several different labora- tories have demonstrated cysteine modifications of Keap1 by inducers (see Sekhar et al. 2010; Holland and Fishbein L. Baird Á A. T. Dinkova-Kostova Biomedical Research Institute, University of Dundee, Dundee, Scotland, UK A. T. Dinkova-Kostova The Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA A. T. Dinkova-Kostova (&) Biomedical Research Institute, Level 5, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK e-mail: a.dinkovakostova@dundee.ac.uk 123 Arch Toxicol (2011) 85:241–272 DOI 10.1007/s00204-011-0674-5