Activator protein-1 mediates induced but not basal epidermal growth factorreceptor gene expression

Background: The epidermal growth factor receptor (EGFR) is expressed at dif ferent levels in many cell types and found overexpressed in many cancers. E GFR expression is increased or decreased in response to extracellular stimu li. We examined the effect of increased c-Jun expression on EGFR promoter a ctivity. Materials and Methods: We used DNAse I footprinting analysis to determine t he binding of activator protein 1 (AP-1) to the promoter region. We also us ed cotransfection experiments and western blotting analysis to determine th e effect of AP-1 family members on EGFR expression. Results: AP-1 was able to bind to at least seven sites in the EGFR promoter region. Cotransfection of MCF-7 cells with a c-Jun expression vector and t he EGFR promoter reporter resulted in a 7-fold increase in promoter activit y. JunB, but not c-fos, also enhanced the EGFR promoter activity. An A-Fos- dominant negative shown to inhibit Jun-dependent transactivation was able t o prevent c-Jun induction of the promoter activity, but only slightly decre ased the basal activity of the promoter. Furthermore, the A-Fos dominant ne gative was able to inhibit phorbol ester induction of the EGFR promoter. Ex amination of EGFR expression of MCF-7 stable cell lines that overexpress c- Jun revealed an increase in EGFR expression. Additionally, a cisplatin-resi stant cell line, A2780/CP70, which has an increase in AP-1 activity compare d with the parental cell line, A2780, was found to have an increase in EGFR level. Conclusions: These results indicate that AP-1 can act to increase the expre ssion of EGFR and may play a role in upregulation of EGFR in cancer cells.