Document Detail


Nrf2-regulated glutathione recycling independent of biosynthesis is critical for cell survival during oxidative stress.
MedLine Citation:
PMID:  19028565     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) is the primary transcription factor protecting cells from oxidative stress by regulating cytoprotective genes, including the antioxidant glutathione (GSH) pathway. GSH maintains cellular redox status and affects redox signaling, cell proliferation, and death. GSH homeostasis is regulated by de novo synthesis as well as GSH redox state; previous studies have demonstrated that Nrf2 regulates GSH homeostasis by affecting de novo synthesis. We report that Nrf2 modulates the GSH redox state by regulating glutathione reductase (GSR). In response to oxidants, lungs and embryonic fibroblasts (MEFs) from Nrf2-deficient (Nrf2(-/-)) mice showed lower levels of GSR mRNA, protein, and enzyme activity relative to wild type (Nrf2(+/+)). Nrf2(-/-) MEFs exhibited greater accumulation of glutathione disulfide and cytotoxicity compared to Nrf2(+/+) MEFs in response to t-butylhydroquinone, which was rescued by restoring GSR. Microinjection of glutathione disulfide induced greater apoptosis in Nrf2(-/-) MEFs compared to Nrf2(+/+) MEFs. In silico promoter analysis of the GSR gene revealed three putative antioxidant-response elements (ARE1, -44; ARE2, -813; ARE3, -1041). Reporter analysis, site-directed mutagenesis, and chromatin immunoprecipitation assays demonstrated binding of Nrf2 to two AREs distal to the transcription start site. Overall, Nrf2 is critical for maintaining the GSH redox state via transcriptional regulation of GSR and protecting cells against oxidative stress.
Authors:
C J Harvey; R K Thimmulappa; A Singh; D J Blake; G Ling; N Wakabayashi; J Fujii; A Myers; S Biswal
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2008-11-05
Journal Detail:
Title:  Free radical biology & medicine     Volume:  46     ISSN:  1873-4596     ISO Abbreviation:  Free Radic. Biol. Med.     Publication Date:  2009 Feb 
Date Detail:
Created Date:  2009-02-02     Completed Date:  2009-11-23     Revised Date:  2013-06-04    
Medline Journal Info:
Nlm Unique ID:  8709159     Medline TA:  Free Radic Biol Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  443-53     Citation Subset:  IM    
Affiliation:
Department of Environmental Health Science, Bloomberg School of Public Health, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Line
Cell Survival / drug effects,  physiology*
Fibroblasts / pathology,  physiology
Glutathione / analogs & derivatives,  biosynthesis,  genetics,  metabolism*
Glutathione Reductase / genetics,  metabolism*
Hydroquinones / pharmacology
Lung / enzymology,  pathology
Mice
Mice, Knockout
Mutagenesis, Site-Directed
NF-E2-Related Factor 2 / genetics,  metabolism*
Oxidation-Reduction
Oxidative Stress / physiology*
Promoter Regions, Genetic / genetics
RNA Interference
RNA, Small Interfering
Response Elements / genetics
Smoking
Transcriptional Activation / physiology
Grant Support
ID/Acronym/Agency:
ES03819/ES/NIEHS NIH HHS; ES07141/ES/NIEHS NIH HHS; F32 HL094018-01/HL/NHLBI NIH HHS; GM079239/GM/NIGMS NIH HHS; HL081205/HL/NHLBI NIH HHS; P50HL084945/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Hydroquinones; 0/NF-E2-Related Factor 2; 0/RNA, Small Interfering; 70-18-8/Glutathione; C12674942B/2-tert-butylhydroquinone; EC 1.8.1.7/Glutathione Reductase
Comments/Corrections

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