Persistent induction of c-fos and c-jun expression by asbestos.

Abstract

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.

Oxygen radicals and asbestos carcinogenesis.

“…Heinz et al discovered increased transcription of c-fos and c-jun in rat pleural mesothelial cells exposed to crocidolite asbestos (38). We have preliminary evidence for increased expression of p53 protein in response to crocidolite asbestos fibers.…”

Role of Inflammation and Angiogenic Growth Factors in Malignant Mesothelioma

“…As reported above, asbestos stimulates the expression of c-fos and c-jun mRNA in mesothelial cells in a dose-dependent fashion (Heintz et al, 1993;Ramos-Nino et al, 2002). One of the mechanisms by which VEGF and PlGF elicit biological responses is the induction of Fos-B and c-Fos expression in endothelial cells and monocytes (Holmes & Zachary, 2004).…”

“…Finally, in mesothelial and lung epithelial cells asbestos fibers, as opposed to nonpathogenic minerals, cause a persistent induction of the redox-sensitive transcription factors NF-κB and Activator Protein-1 (AP-1), which is accompanied by chronic alterations in gene expression (Heintz et al, 1993;Janssen et al, 1995). As mentioned above, the aberrant activation of the NF-κB pathway is regarded as a critical event for mesothelial cell transformation (Toyooka et al, 2008).…”

“…AP-1 is a redox-sensitive transcription factor typically associated with cell proliferation and tumor promotion (Eferl & Wagner, 2003). The first evidence showing that asbestos exerts regulatory effects linked to aberrant transcriptional responses, cell proliferation and cell transformation derives from studies in which asbestos fibers caused induction of c-fos and cjun proto-oncogene mRNAs in pleural mesothelial cells and tracheo-bronchial epithelial cells in a dose-response fashion (Heintz et al, 1993).…”

Molecular biology of malignant mesothelioma

“…JUN is a transcription factor and functions as homo-or hetero-dimerization with FOS to form the transcription factor AP-1, which can bind to the promoter region of intermediate genes involved in cell division and other cell functions. Both crocidolite and chrysotile asbestos reportedly caused increases in the expression of JUN and FOS in rat pleural mesothelial cells [29]. Since the gene amplification of JUN was identified in a subset of MPM tumors, it was suggested that there were some strong and persistent factors for JUN activation during the development of MPM tumor cells.…”