Function and signal transduction of Nrf2 from a metal's perspective.
Toxicologist 2008 Mar; 102(1):130
Metals comprise a large group of environmental and occupational toxicants; many are human carcinogens. Although the mechanism by which metals cause cancer and toxicity remains unclear, oxidative damage is known to be a critical component of metal action. In recent years, Nrf2 has emerged as a prooxidant/antioxidant-activated receptor/transcription factor that integrates a variety of oxidative stimuli from both exogenous and endogenous sources and coordinately regulates the antioxidant response element-dependent transcription of a battery of cytoprotective genes, thereby protecting cells from oxidative stress and damage. The function and signal transduction of Nrf2 in response to carcinogenic metals were analyzed in this study, with focus on transcriptional protective mechanisms against metal-induced oxidative stress by Nrf2 and the molecular events of Nrf2 activation by toxic metals. Exposure to carcinogenic metals such as As, Cr, and Cd induces apoptosis and increased production of ROS. Loss of Nrf2 by gene knockout and SiRNA knockdown markedly increases the ROS production and cell death in the presence of the metals. Metals activate Nrf2 by stabilizing the Nrf2 protein via a signaling mechanism distinctively different from that of phenolic antioxidants in that metals disrupt Nrf2/Keap1 association in the nucleus whereas phenolic inducers do not. Both Nrf2 and Keap1 are ubiquitinated in the cytoplasm; upon activation, the two proteins translocate into the nucleus in a complex and are deubiquitinated in the nucleus. Chromatin immunoprecipitation revealed binding of Nrf2 and Maf G/K to the ARE located in the enhancers of Nqo1 and Ho1 for gene transcription. The findings suggest a unique molecular model of metal action in metal sensing and transcriptional gene regulation in mammalian cells.
Cell-biology; Cell-transformation; Cellular-reactions; Cell-alteration; Pathogenicity; Pathogens; Pathomorphology; Molecular-biology; Molecular-structure; Pulmonary-system-disorders; Lung-fibrosis; Genotoxic-effects; Genotoxicity; Cancer; Carcinogenicity; Carcinogenesis; Carcinogens; Metal-dusts; Metal-fumes; Metal-poisoning; Metallic-dusts; Metallic-poisoning
The Toxicologist. Society of Toxicology 47th Annual Meeting and ToxExpo, March 16-20, 2008, Seattle, Washington