Breast Cancer: Involvement of Epidermal Growth Factor Receptor, MDM2 and P53 Mutations.
Annual rept. 15 Sep 94-14 Sep 95,
TEXAS UNIV HEALTH SCIENCE CENTER AT SAN ANTONIO
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The epidermal growth factor receptor EGFR is a transmembrane glycoprotein with an extracellular epidermal growth factor EGF-binding domain and an intracellular protein tyrosine kinase domain. EGF stimulates cell proliferation by directly activating EGFR, leading to signal transduction through an intracellular cascade of second messengers. It was previously demonstrated that the wild-type human pS3 tumor suppressor can transactivate the human EGFR promoter through a p53-response element mapped to the region from -569 to -104, relative to the translational start site. Further analysis has identified the 27-base pair region from -265 to -239 as the p53-binding siteresponse element. This region possesses sequence homology to a p53- binding siteresponse element in the human retinoblastoma susceptibility Rb gene promoter, and is responsive to wild-type pS3 when cloned upstream of a minimal heterologous promoter. Mobility-shift and DNase I footprinting assays indicated that wild-type pS3 binds directly to the response element. The p53-binding siteresponse element overlaps the binding sites for both positive ETF and negative GCF regulators of EGFR promoter activity, and contains or borders the most 5 of the EGFR in vivo transcriptional start sites.
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