Document Detail

The gamma-glutamylcysteine synthetase and glutathione regulate asbestos-induced expression of activator protein-1 family members and activity.
MedLine Citation:
PMID:  15520183     Owner:  NLM     Status:  MEDLINE    
Asbestos fibers cause persistent increases in activator protein-1 (AP-1) family member proto-oncogenes in lung epithelial and mesothelial cells that are linked to proliferation and cell transformation. Using lung epithelial cells, the progenitor cells of lung cancers, we report that crocidolite asbestos initially depletes intracellular glutathione followed by up-regulation of both catalytic and modifier subunits of gamma-glutamylcysteine synthetase. In vivo asbestos inhalation experiments confirm increased protein levels of gamma-glutamylcysteine synthetase in mouse lungs. We also show that asbestos-induced mRNA levels of fos/jun proto-oncogenes, fra-1 transactivation, and AP-1 to DNA binding activity are glutathione-dependent. Epidermal growth factor receptor activity by asbestos is blocked by N-acetyl-l-cysteine, suggesting that it is an initial redox-activated event leading to downstream AP-1 proto-oncogene up-regulation. The overexpression of subunits of gamma-glutamylcysteine synthetase in combination completely blocked asbestos-induced up-regulation of AP-1 proto-oncogene expression. However, when overexpressed individually, the modifier subunit had more dramatic effects than the catalytic subunit. Our work shows that the glutathione-controlled redox status of the epithelial cell plays a pivotal role in asbestos-induced epidermal growth factor receptor and proto-oncogene activation as well as AP-1 activity.
Arti Shukla; Trisha Flanders; Karen M Lounsbury; Brooke T Mossman
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Cancer research     Volume:  64     ISSN:  0008-5472     ISO Abbreviation:  Cancer Res.     Publication Date:  2004 Nov 
Date Detail:
Created Date:  2004-11-02     Completed Date:  2004-11-30     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  7780-6     Citation Subset:  IM    
Department of Pathology, University of Vermont, Burlington, Vermont 05405, USA.
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MeSH Terms
Acetylcysteine / pharmacology
Asbestos / toxicity*
Buthionine Sulfoximine / pharmacology
DNA / metabolism
Glutamate-Cysteine Ligase / genetics,  physiology*
Glutathione / analysis,  physiology*
Proto-Oncogene Proteins c-fos / genetics
Receptor, Epidermal Growth Factor / metabolism
Transcription Factor AP-1 / metabolism*
Transcriptional Activation
Grant Support
Reg. No./Substance:
0/Proto-Oncogene Proteins c-fos; 0/Transcription Factor AP-1; 0/fos-related antigen 1; 1332-21-4/Asbestos; 5072-26-4/Buthionine Sulfoximine; 616-91-1/Acetylcysteine; 70-18-8/Glutathione; 9007-49-2/DNA; EC, Epidermal Growth Factor; EC Ligase

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