Transcription factor AP-2 controls transcription of the human transforming growth factor-alpha gene

The epidermal growth factor receptor is vital for normal development and plays a role in oncogenesis, The level of activation of this receptor by transforming growth factor-alpha (TGF-alpha) is controlled, in part, by the rate of transcription of the TGF-alpha gene, In the characterization of the proximal TGF-alpha promoter by DNase I footprinting, a 43-base pair element (-88 to -130 relative to the transcription start site), designated T alpha RE I, was found that was specifically protected by nuclear proteins from human mammary carcinoma MDA468 cells, T alpha RE I was essential for the maximal expression of the TGF-alpha gene as indicated by deletion and mutagenesis analyses, T alpha RE I consists of two cis-acting elements, a proximal regulatory element (PRE, -89 to -103) and a distal regulatory element (DRE, -121 to -128), Both elements were able to form specific complexes with protein from MDA468 cell nuclear extracts and are necessary for the full activity of the entire 1.1-kilobase pair TGF-alpha promoter, Competition and antibody studies determined that the DRE contains a binding site for the transcription factor AP 2, while the protein that binds to the PRE has yet to be identified, When linked upstream to the heterologous herpes simplex thymidine kinase promoter, the T alpha RE I enhanced transcription up to 11-fold in MDA468 cells, Cotransfection of an AP-2 expression vector was able to activate transcription from the T alpha REI-TK construct in a DRE-dependent manner. These results further our understanding of how TGF-alpha transcription is regulated.