Fig. 2

Signal transduction pathways responsible for Nrf2-ARE activation. Nrf2 activation is regulated by two distinct cellular signaling pathways in a manner similar to that applied to NF-κB activation signaling schematically represented in Fig. 1. Upon stimulation of cells, activation of protein kinases such as PI3K, PKC, JNK, p38MAPK and ERK induce Nrf2 phosphorylation, which facilitates the dissociation of Nrf2 from its repressor Keap1 and subsequent translocation to nucleus and interaction with the coactivator CBP/p300. Alternatively, prooxidants or electrophiles may directly interact with cysteine residues present in Keap1, thereby stimulating Nrf2 dissociation. Both events can facilitate the nuclear translocation of Nrf2, which subsequently associates with small Maf, forming a heterodimer binds to antioxidant-response element (ARE) or electrophile-responsive element (EpRE) to stimulate phase II detoxification or antioxidant enzymes. Chemopreventive phytochemicals can activate Nrf2 signaling by inducing phosphorylation of Nrf2 via activation of the upstream kinases and/or through oxidation/modification of Keap1 cysteine thiols