Persistent induction of c-fos and c-jun expression by asbestos.
To investigate the mechanisms of asbestos-induced carcinogenesis, expression of c-fos and c-jun protooncogenes was examined in rat pleural mesothelial cells and hamster tracheal epithelial cells after exposure to crocidolite or chrysotile asbestos. In contrast to phorbol 12-myristate 13-acetate, which induces rapid and transient increases in c-fos and c-jun mRNA, asbestos causes 2- to 5-fold increases in c-fos and c-jun mRNA that persist for at least 24 hr in mesothelial cells. The induction of c-fos and c-jun mRNA by asbestos in mesothelial cells is dose-dependent and is most pronounced with crocidolite, the type of asbestos most pathogenic in the causation of pleural mesothelioma. Induction of c-jun gene expression by asbestos occurs in tracheal epithelial cells but is not accompanied by a corresponding induction of c-fos gene expression. In both cell types, asbestos induces increases in protein factors that bind specifically to the DNA sites that mediate gene expression by the AP-1 family of transcription factors. The persistent induction of AP-1 transcription factors by asbestos suggests a model of asbestos-induced carcinogenesis involving chronic stimulation of cell proliferation through activation of the early response gene pathway that includes c-jun and/or c-fos.
Department of Pathology, University of Vermont College of Medicine, Burlington 05405.
N H
NH
Heintz
Y M
YM
Janssen
B T
BT
Mossman
D000818:Animals; D001194:Asbestos / Q000494:pharmacology* / Q000633:toxicity*; D017638:Asbestos, Crocidolite; D017632:Asbestos, Serpentine; D015152:Blotting, Northern; D002455:Cell Division / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells; D004848:Epithelium / Q000187:drug effects / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects; D016762:Genes, fos / Q000187:drug effects*; D016758:Genes, jun / Q000187:drug effects*; D007700:Kinetics; D008954:Models, Biological; D010994:Pleura / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis* / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D014132:Trachea / Q000166:cytology / Q000187:drug effects* / Q000502:physiology
D017632:Asbestos, Serpentine; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D017638:Asbestos, Crocidolite; D001194:Asbestos