Trends in Molecular Medicine
Nrf2–Keap1 defines a physiologically important stress response mechanism
Section snippets
Nrf2 as a key regulator of phase II detoxifying enzyme genes and antioxidant-responsive genes
The DNA binding domain of Nrf2 is similar to those of the other CNC family members [6]. Therefore, these transcription factors are likely to interact with the ARE, giving rise to elaborate defence regulation against xenobiotic and oxidative stresses. The contribution of the four CNC proteins p45, Nrf1, Nrf2 and Nrf3 to the regulation of ARE-dependent genes was examined in vivo by gene targeting (Box 2) 5, 15, 16, 17, 18, 19. Germline mutagenesis of the mouse nrf2 gene and examination of the
Transcriptional activation by Nrf2 and its related CNC proteins
Nrf2 contains two activation domains, Neh4 and Neh5, both of which are conserved in various Nrf2 proteins in several species (Figure 1a) [27]. Both Neh4 and Neh5 can bind to the coactivator CBP [cAMP-response-element binding protein (CREB) binding protein] independently, and simultaneous binding of CBP to these two domains synergistically activates the transcription of Nrf2 target genes. We surmise that Nrf2 achieves strong transactivation activity, at least in part, through this mechanism.
Inhibition of Nrf2 activity by the actin-binding protein Keap1
Structure–function analyses of Nrf2 revealed that deletion of the N-terminal region (Neh2 domain) enhances the transcriptional activity of Nrf2 (Figure 1a). Keap1, a novel cytoplasmic protein, was subsequently identified as an Neh2-interacting molecule [31]. Keap1 possesses a BTB (broad complex–tramtrack–bric-a-brac) domain and double glycine repeat (DGR) domain in its N-terminus and C-terminus, respectively (Figure 1b). The DGR domain is important for the interaction with Nrf2 and also for
Molecular mechanisms of Nrf2 activation
Extensive analyses of nrf2-null mutant mice have revealed that the inducible expression of detoxifying enzyme genes and antioxidant responsive genes is important for protection against carcinogenesis and the toxicity arising from electrophiles and oxidants. Under basal conditions, Nrf2-mediated transcription is turned off because of the inhibitory effect of Keap1. Keap1 binds to Nrf2 and sequesters the molecule from nuclei, preventing Nrf2 from activating target genes [31]. Recent studies
New perspectives for Nrf2–Keap1
The analyses of nrf2-null mutant mice have revealed that the genes regulated by Nrf2 are indispensable components of defence mechanisms against oxidative and xenobiotic stresses. It has been predicted that specific inducers of Nrf2 would make good chemoprotective reagents against ROS and chemical carcinogens. Although the chemopreventive effects of BHA and oltipraz are recognized [13], recent screenings identified many dietary and synthetic compounds that efficiently activate Nrf2 58, 59. The
Concluding remarks
Recent data support the contention that the Nrf2–Keap1 system serves as an indispensable part of the defence mechanisms against various environmental, as well as endogenous, stresses. The activation of Nrf2 is a key initiation step in the cellular response against such insults. Nrf2 deficiency leads to several common pathogenic conditions, including susceptibility to chemical carcinogenesis 13, 21, acute hepatotoxicity after medication 10, 11, acute respiratory distress following the ingestion
Acknowledgements
We thank Paul Talalay, Tom Kensler, John Hayes, Doug Engel and our laboratory members for generous advice. We also thank Ken Itoh and Akira Kobayashi for discussion and advice, and Kit I. Tong for help. We apologize for not citing many important publications in this emerging field owing to the space limitation. This work has been supported in part by grants from ERATO-JST, MEXT, MHLW and JSPS.
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