TRANSCRIPTIONAL CONTROL OF THE HUMAN BILIARY GLYCOPROTEIN GENE, A CEAGENE FAMILY MEMBER DOWN-REGULATED IN COLORECTAL CARCINOMAS

Biliary glycoprotein (BGP) isoantigens are derived by alternative spli cing from a single gene and are the human homologs of rat C-CAM and th e mouse Bgp species. These glycoproteins represent a family of cell-ad hesion molecules. The mouse Bgp isoforms also act as receptors for the hepatitis viral capsid-protein. BGP is a member of the carcinoembryon ic antigen (CEA) gene family, which belongs to the immunoglobulin supe rgene family, yet it displays restricted expression patterns and uniqu e functions. Since the loss or reduced expression of BGP is associated with human colorectal carcinomas, the elements in its upstream regula tory region were analyzed. A cluster of transcriptional initiation sit es and the minimal promoter, located within 150 bp upstream of the maj or transcriptional start site, were active in human colon carcinoma an d hepatoma cells. Unlike the CEA gene, BGP gene transcription was not modulated by a silencer region; repetitive elements in the BGP upstrea m region were not involved in activation or repression. Footprinting e xperiments identified two cis-acting elements and mobility-shift assay s demonstrated that these elements bound several transcription factors , among them, USE HNF-4 and an AP-2-like factor. In cotransfection exp eriments, both the USF and HNF-4 transcription factors transactivate t he BGP gene promoter and compete for the same regulatory element. The Sp1 transcription factor, shown to be involved in CEA gene transcripti onal regulation, does not bind to the BGP gene promoter. We, therefore , propose that the relative distributions and interactions of these tr anscription factors mediate distinct transcriptional regulation of the BGP gene in colon and liver; this regulation could be distorted durin g the oncogenic process.