The Nrf2-Keap1 signalling pathway: Mechanisms of ARE transcription regulation in antioxidant cellular defence

The Nrf2-Keap1 [Nuclear factor E2-related factor 2-Kelch like ECH-associated protein 1] pathway is the main regulator of cytoprotective responses to electrophilic and oxidative insults. Nrf2 regulates the expression of detoxifying enzymes by recognizing the human antioxidant response element (ARE) binding site and it can regulate antioxidant and anti-inflammatory cellular responses, playing an important protective role on the development of various diseases such as cancer. Briefly, under homeostatic conditions, Nrf2 is suppressed by association with its inhibitory partner keap1, but is stimulated upon exposure to oxidative orelectrophilic stress. Once activated, Nrf2 binds to ARE sites in the promoter regions of various detoxification and antioxidant genes, leading to the induction of multiple target cytoprotective genes that boost cellular detoxification processes and antioxidant potential. In this current review, we provide an overview on the Nrf2-Keap1-ARE transcription pathway. We also briefly summarize the mechanisms of Nrf2 transcription regulation and the involvement of multiple stress-mediated cell signaling kinase cascades with Keap1 in regulating Nrf2 activity.