Adenovirus EIA down-regulates the EGF receptor via repression of its promoter

The epidermal growth factor receptor (EGF-R), after activation by its ligan ds, stimulates a cascade of intracellular events leading to cellular prolif eration, Its expression is increased in various forms of cancer as a conseq uence of altered regulation. Our objective was to study potential negative regulators of EGF-IR expression; we investigated the effect of adenovirus E 1A proteins, E1A proteins can exert both positive and negative effects on c ell growth, depending on the cell type;md cellular context, and have anti-t umorigenic features on human cancer cells. We show that human cell lines st ably transformed with the adenovirus E1 region show significantly reduced e xpression of EGF-R protein and mRNA compared to their control, non-E1A-expr essing counterparts. Furthermore, the promoter activity of EGF-R can be spe cifically repressed by E1A in transient co-transfection analysis in multipl e cell types, Transfections with deleted promoter fragments and constructs containing short fragments of the putative E1A-responsive region fused to a heterologous promoter indicate that E1A-responsive elements are contained in a promoter region (from -150 to -76). Analysis of E1A mutants showed tha t both E1A gene products, 12S and 13S, repress EGF-R promoter activity and that full repression requires the presence of an intact CR1 domain, Int. J, Cancer 88:943-948, 2000. (C) 2000 Wiley-Liss Inc.