Figure 5: Operation of the Nrf2/Keap1 system during response to oxidative stress in animals. Under nonstressed conditions the transcription factor Nrf2 binds to the Keap1 homodimer. The resulting protein complex can then further complex with Cullin 3 leading to ubiquitination of Nrf2 followed by proteasomal degradation. Following an oxidative insult or electrophilic attack, Keap1 cannot bind Nrf2 which allows Nrf2 to diffuse into the nucleus and, in concert with small Maf proteins (sMaf), Map and others, Nrf2 binds to the ARE/EpRE elements of regulatory regions in genes encoding antioxidant or phase 2 detoxification enzymes. Nrf2 migration into the nucleus is promoted by at least three different mechanisms: oxidation of Keap thiol groups to form disulfides, modification of Keap1 cysteine residues by electrophiles, or phosphorylation of Nrf2 by protein kinases that, in turn, may be activated by oxidants.