Role of the Nrf2 signaling system in health and disease.

A key component of cytoprotective gene regulation is the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), also known as nuclear factor erythroid 2-like 2, from the gene NFE2L2. Under normal conditions, Nrf2 in the cell is targeted for proteasomal degradation by its inhibitor Kelch-like ECH-associated inhibitor 1 (Keap1). When stimulated by oxidative stress, electrophiles, or kinase activation, conformational changes in the Nrf2-Keap1 complex inhibit proteasomal degradation of Nrf2, facilitating an increase in the amount of Nrf2 that binds to antioxidant response element sequences in the promoter regions of a variety of antioxidant, detoxification, and metabolic control genes. Nrf2 activation is mostly associated with beneficial cytoprotective gene regulation, but it can also have deleterious effects. For example, gene mutations in some types of cancers can lead to constitutive activation of Nrf2 and give the tumor cells growth advantages and increased drug resistance. Because cases exist where Nrf2/Keap1/ARE signaling is either too low or too high, there is great interest in the development of both Nrf2 activators and Nrf2 inhibitors as the basis of new therapies.