FIG. 5.

Schematic representation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant responsive element (ARE) pathway and ARE-induced gene expression. Environmental stress exerts oxidative stress on cells through production of reactive oxygen and nitrogen species (RONS). The oxidative stress response is largely coordinated by a transcription factor, Nrf2. Under homeostatic conditions, there is only an inactive minimal basal level of Nrf2-directed gene expression under tight control of the protein Keap 1. RONS lead to the activation of mitogen-activated protein kinases (MAPK, ERK, p38), protein kinase C (PKC), phosphatidylinositol 3 kinase (PI3K), and others, which phosphorylate Keap1 and Nrf2. The Keap1-Nrf2 complex is then disrupted and the transcriptionally active Nrf2 is translocated to the nucleus where it binds to AREs in association with Maf proteins. This results in an increase of the transcriptional expression of Nrf2-inducible genes such as those encoding heme oxygenase-1 (HMOX1), NAD(P)H quinone oxidoreductase (NQO1), and glutathione-S-transferase A2 (GSTA2). Together, these proteins scavenge RONS and limit oxidative damage.