Protection against chromium (VI)-induced oxidative stress and apoptosis by Nrf2. Recruiting Nrf2 into the nucleus and disrupting the nuclear Nrf2/Keap1 association.
Chromium (Cr) (VI) is a major environmental toxic metal and a human carcinogen. The molecular events mediating cellular responses to Cr(VI) are not clear at present. We show that Cr(VI) potently induced apoptosis and production of reactive oxygen species (ROS) in mouse hepa1c1c7 cells in a concentration-dependent manner. Mouse embryonic fibroblast cells lacking Nrf2 exhibited elevated ROS production and apoptosis, which were markedly further increased by Cr(VI), suggesting a protective role of Nrf2 against Cr(VI) toxicity. Protection by Nrf2 correlated with induction of cytoprotective genes Ho-1 and Nqo1. Induction of the genes by Cr(VI) involved inhibition of ubiquitination of Nrf2 and accumulation of Nrf2 into the nucleus. In the nucleus, treatment with Cr(VI), but not phenolic antioxidant tert-butylhydroquinone, librates Nrf2 from the Nrf2/Keap1 association and recruits Nrf2 to the antioxidant response elements (ARE) located in the enhancers of Ho-1 and Nqo1. Activation of Nrf2 by Cr(VI) was accompanied by the nuclear translocation and deubiquitination of Keap1 implicating recycling of Keap1 in Nrf2 signaling. Thus, protection against Cr(VI) toxicity involves a transcriptional signaling loop that includes activation of Nrf2 by the toxic metal, transcription of ARE-driven genes, and reduction of ROS production.
He
Xiaoqing
X
Receptor Biology Laboratory, Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, West Virginia 26505, USA.
Lin
Gary X
GX
Chen
Michael G
MG
Zhang
Jennifer X
JX
Ma
Qiang
Q
D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015152:Blotting, Northern; D015153:Blotting, Western; D002458:Cell Fractionation; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D002843:Chromatin / Q000378:metabolism; D002857:Chromium / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D045304:Cytochromes c / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D051547:Heme Oxygenase-1 / Q000378:metabolism; D047468:Immunoprecipitation; D000072019:Kelch-Like ECH-Associated Protein 1; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects*; D010957:Plasmids / Q000235:genetics; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D014162:Transfection
D048868:Adaptor Proteins, Signal Transducing; D000975:Antioxidants; D002843:Chromatin; D003598:Cytoskeletal Proteins; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D002857:Chromium; D012313:RNA; D045304:Cytochromes c; D051547:Heme Oxygenase-1