A mutant epidermal growth factor receptor targeted to lung epithelium inhibits asbestos-induced proliferation and proto-oncogene expression.
Asbestos is a ubiquitous naturally occurring fiber causing multiple cancers and fibroproliferativedisease. The mechanisms of epithelial cell hyperplasia, a hallmark of the initiation of lung cancers by asbestos, have been unclear. We demonstrate here that mice expressing a dominant-negative mutant epidermal growth factor receptor (EGFR) under the control of the human lung surfactant protein-C promoter exhibit decreased pulmonary epithelial cell proliferation without alterations in asbestos-induced inflammation. In contrast to transgene-negative littermates, inhalation of asbestos by mice expressing the mutant EGFR does not result in early and elevated expression of early response proto-oncogenes (fos/jun or activator protein 1 family members). Additionally, quantitative reverse transcriptase-PCR analysis for levels of c-jun and c-fos in bronchiolar epithelium isolated by laser capture microdissection demonstrates increases in expression of these genes in asbestos-exposed epithelial cells. Results show that the EGFR mediates both asbestos-induced proto-oncogene expression and epithelial cell proliferation, providing a rationale for modification of its phosphorylation in preventive and therapeutic approaches to lung cancers and mesothelioma.
Manning
Christopher B
CB
Department of Pathology, University of Vermont, Burlington, Vermont 05405, USA.
Cummins
Andrew B
AB
Jung
Michael W
MW
Berlanger
Ingrid
I
Timblin
Cynthia R
CR
Palmer
Cathy
C
Taatjes
Douglas J
DJ
Hemenway
David
D
Vacek
Pamela
P
Mossman
Brooke T
BT
D000280:Administration, Inhalation; D000818:Animals; D017638:Asbestos, Crocidolite / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D016762:Genes, fos / Q000187:drug effects; D016758:Genes, jun / Q000187:drug effects; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation; D011014:Pneumonia / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D000090063:Proto-Oncogene Mas; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis* / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000099169:Fos-Related Antigen 1
D017638:Asbestos, Crocidolite; D066246:ErbB Receptors; D020929:Mitogen-Activated Protein Kinase Kinases; D000090063:Proto-Oncogene Mas; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D000099169:Fos-Related Antigen 1; C000715470:MAS1 protein, human