Figure 2

Schematic presentation of Nrf2-ARE pathway. In the cytoplasm, under basal level, newly synthesized Nrf2 is constitutively bound to Keap1 forming a dimer, Nrf2-Keap1. Keap1 is a cytosolic protein that inhibits Nrf2 signalling by promoting Nrf2 degradation through proteasomal pathway. When oxidants such as ROS, RNS and dietary chemopreventive compounds react with redox reactive cysteines in Keap1, Nrf2 will be released from Keap1, hence allowing the transcriptional factor Nrf2 to translocate to the nucleus. In the nucleus, Nrf2 dimerizes with basic leucine zipper partners (bZip) such as small MAF-family proteins and bind to ARE, which is located in the promoter of the phase II and antioxidative genes, triggering the transcription of ARE-regulated genes. The critical role of Nrf2 in protecting cells/subjects from neoplastic transformation when subject to oxidative stress and carcinogens is performed by enhancing the expression of detoxifying metabolizing enzymes and maintaining oxidative stress homeostasis by producing antioxidant enzymes. Application of chemopreventive compounds can further enhance the expression of phase II detoxifying and antioxidant enzymes by up-regulating the Nrf2-ARE expression.