NF-E2 related factor 2 (Nrf2) is a member of the cap n collar, basic leucine zipper family of transcription factors. Nrf2 mediates gene regulation by a range of chemicals with diverse structures. Activation of Nrf2 by phenolic and other antioxidants involves redox signaling. Induction of phase 2 drug-metabolizing enzyme NQO1, which catalyzes two electron reductions of quinone and quinoid chemicals, is used as a model for analyzing mechanism of gene transcription by Nrf2. Biochemical and genetic evidence demonstrate Nrf2 is required for three types of transcription of the gene: the basal expression, induction by antioxidants, and induction by AhR ligands, suggesting it serves as a master regulator of multiple signal transduction pathways in the transcription of target genes. Loss of Nrf2 function by targeted gene knock out increases the sensitivity of mice and cells to toxicity of oxidative chemicals. Moreover, Nrf2 null mice develop an early-onset, Lupus-like, autoimmune syndrome, characterized by appearance of anti-double strand DNA antibodies in young adulthood (as early as 2 month of age), multi-organ inflammatory lesions, enhanced proliferation of lymphoid cells, deposition of immunoglobulin complexes in glomerular membranes, and death due to rapid progressing, diffuse membranoglomerular nephritis. Taken together, these findings suggest Nrf2 plays critical roles in maintaining cellular homeostasis to oxidative toxicants and in physiological surveillance of autoimmune functions.
The Toxicologist. Society of Toxicology 43nd Annual Meeting and ToxExpo, March 21-25, 2004, Baltimore, Maryland