Protection against electrophile and oxidative stress by induction of phase 2 genes: The quest for the elusive sensor that responds to inducers

Phase 2 genes and their products comprise ubiquitous and elaborate mechanisms that protect cells against the damaging effects of electrophiles and oxidants that underlie the genesis of cancer and other chronic degenerative diseases. Induction of these genes is a highly effective strategy for protecting cells against these stressors. Phase 2 proteins comprise not only the classical enzymes that conjugate the products of cytochrome P450 action with endogenous ligands such as glutathione and glucuronic acid, but also a wide variety of proteins that disable oxidants or generate antioxidants such as GSH and contribute to its function. The chemistry of phase 2 gene inducers is highly varied, but characterized by one universal property: all inducers react with thiol groups (by alkylation or oxidoreduction reactions), and it was suspected therefore that the cellular "sensor" for inducers must contain highly reactive cysteine residues. Keap1 is a multi-domain, cysteine-rich protein that resides in the cytoplasm bound to the actin cytoskeleton through its Kelch domain, and contains highly reactive cysteine residues in its intervening domain. Inducers react with these thiols leading probably to conformational change in Keap1 and ultimately to dissociation from its partner, the transcription factor Nrf2. Nrf2 then undergoes nuclear translocation, binds in heterodimeric combinations with members of the small Maf family of nuclear factors, to the 5′-upstream AREs, and activates the transcription of phase 2 genes.