The Keap1-Nrf2 pathway is the major regulator of cytoprotective responses to oxidative and electrophilic stress. Although cell signaling pathways triggered by the transcription factor Nrf2 prevent cancer initiation and progression in normal and premalignant tissues, in fully malignant cells Nrf2 activity provides growth advantage by increasing cancer chemoresistance and enhancing tumor cell growth. In this graphical review, we provide an overview of the Keap1-Nrf2 pathway and its dysregulation in cancer cells. We also briefly summarize the consequences of constitutive Nrf2 activation in cancer cells and how this can be exploited in cancer gene therapy.

Nitro-fatty acids (NOIn this study, we investigate the molecular mechanisms by which 9-and 10-nitro-octadec-9-enoic acid (OA-NO 2 ) activate the transcription factor Nrf2, focusing on the post-translational modifications of cysteines in the Nrf2 inhibitor Keap1 by nitroalkylation and its downstream responses. Of the two regioisomers, 9-nitrooctadec-9-enoic acid was a more potent ARE inducer than 10-nitro-octadec-9-enoic acid. (2), the enzyme xanthine oxidoreductase (3), and the transcription factor peroxisome proliferator-activated receptor ␥ (PPAR␥) (4). Moreover, NO 2 -FAs activate heat shock (5) and antioxidant response pathways (5, 6) via mechanisms that remain to be defined. Antioxidant response element (ARE)-regulated genes play an essential role in the protection against endogenous and exogenous stresses (7). The transcription factor nuclear factor E2-related factor-2 (Nrf2) can activate these genes via binding to AREs as a heterodimer with small Maf proteins (7). Under basal conditions, Nrf2 is bound to its inhibitor Kelch-like ECHassociated protein 1 (Keap1), which functions as an adaptor molecule in the Cul3-based E3 ligase complex. Nrf2 is then rapidly ubiquitinated and degraded (8, 9). During periods when cellular concentrations of oxidative or electrophilic species are elevated, the interaction of Nrf2 with the ubiquitin ligase complex is disrupted, enabling the escape of Nrf2 from degradation, its nuclear translocation, and transactivation of target genes.Keap1 is a Cys-rich protein with 27 Cys residues in the human and 25 Cys residues in the murine protein. Keap1 has four functional domains: the Bric-a-Brac, tramtrack, broad complex (BTB) domain, the intervening region (IVR), the Kelch domain (also known as the double glycine repeat), and the C-terminal region. Alkylation or oxidation of Keap1 Cys residues, predominantly within the IVR, leads to the inactivation of Keap1 and is the central mechanism for the activation of Nrf2 (10 -12). A number of studies utilizing mass spectrometry (MS) analysis show that electrophilic inducers of Nrf2 modify several different Cys residues in recombinant Keap1. These data indi-* This work was supported, in whole or in part, by National Institutes of Health BTB, Bric-a-Brac, tramtrack, broad complex; IVR, intervening region; 15d-PGJ 2 , 15-deoxy-⌬12,14-prostaglandin J 2 ; HEK, human embryonic kidney; ␤-ME, ␤-mercaptoethanol; OA-NO 2 , 9-and 10-nitro-octadec-9-enoic acid; 9-OA-NO 2 , 9-nitro-octadec-9-enoic acid; 10-OA-NO 2 , 10-nitro-octadec-9-enoic acid; LNO 2 , 9-, 10-, 12-, or 13-nitro-octadeca-9,12-dienoic acid.

Redox networks in the cell integrate signaling pathways that control metabolism, energetics, cell survival, and death. The physiological second messengers that modulate these pathways include nitric oxide, hydrogen peroxide, and electrophiles. Electrophiles are produced in the cell via both enzymatic and nonenzymatic lipid peroxidation and are also relatively abundant constituents of the diet. These compounds bind covalently to families of cysteine-containing, redox-sensing proteins that constitute the electrophile-responsive proteome, the subproteomes of which are found in localized intracellular domains. These include those proteins controlling responses to oxidative stress in the cytosol—notably the Keap1-Nrf2 pathway, the autophagy-lysosomal pathway, and proteins in other compartments including mitochondria and endoplasmic reticulum. The signaling pathways through which electro-philes function have unique characteristics that could be exploited for novel therapeutic interventions; however, development of such therapeutic strategies has been challenging due to a lack of basic understanding of the mechanisms controlling this form of redox signaling. In this review, we discuss current knowledge of the basic mechanisms of thiol-electrophile signaling and its potential impact on the translation of this important field of redox biology to the clinic. Emerging understanding of thiolelectrophile interactions and redox signaling suggests replacement of the oxidative stress hypothesis with a new redox biology paradigm, which provides an exciting and influential framework for guiding translational research.

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