Skip Navigation


ToxSci Advance Access originally published online on April 9, 2007
Toxicological Sciences 2007 98(1):298-309; doi:10.1093/toxsci/kfm081
This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
98/1/298    most recent
kfm081v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (2)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by He, X.
Right arrow Articles by Ma, Q.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by He, X.
Right arrow Articles by Ma, Q.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Protection against Chromium (VI)–Induced Oxidative Stress and Apoptosis by Nrf2. Recruiting Nrf2 into the Nucleus and Disrupting the Nuclear Nrf2/Keap1 Association

Xiaoqing He, Gary X. Lin, Michael G. Chen, Jennifer X. Zhang2 and Qiang Ma1

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, Mailstop 3014, 1095 Willowdale Road, West Virginia 26505

1 To whom correspondence should be addressed. Fax: (304) 285-5708. E-mail: qam1{at}cdc.gov.

Received February 2, 2007; accepted March 22, 2007


  Abstract

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.

Key Words: chromium; Nrf2; gene induction; antioxidant response; chromatin immunoprecipitation; ubiquitin.

2 Present address: Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer:
Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.