This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shukla, A. Articles by Mossman, B. T. Search for Related Content PubMed PubMed Citation Articles by Shukla, A. Articles by Mossman, B. T.

The -Glutamylcysteine Synthetase and Glutathione Regulate Asbestos-induced Expression of Activator Protein-1 Family Members and Activity

Departments of ¹ Pathology and ² Pharmacology, University of Vermont, Burlington, Vermont

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 -glutamylcysteine synthetase. In vivo asbestos inhalation experiments confirm increased protein levels of -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 -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.

This article has been cited by other articles:

				P. Nymark, H. Wikman, S. Ruosaari, J. Hollmen, E. Vanhala, A. Karjalainen, S. Anttila, and S. Knuutila Identification of Specific Gene Copy Number Changes in Asbestos-Related Lung Cancer Cancer Res., June 1, 2006; 66(11): 5737 - 5743. [Abstract] [Full Text] [PDF]

				B. T. Mossman, K. M. Lounsbury, and S. P. Reddy Oxidants and Signaling by Mitogen-Activated Protein Kinases in Lung Epithelium Am. J. Respir. Cell Mol. Biol., June 1, 2006; 34(6): 666 - 669. [Abstract] [Full Text] [PDF]