Transcriptional control of the human biliary glycoprotein gene, a CEA gene family member down‐regulated in colorectal carcinomas

Abstract

Biliary glycoprotein (BGP) isoantigens are derived by alternative splicing from a single gene and are the human homologs of rat C-CAM and the mouse Bgp species. These glycoproteins represent a family of cell-adhesion molecules. The mouse Bgp isoforms also act as receptors for the hepatitis viral capsid-protein. BGP is a member of the carcinoembryonic antigen (CEA) gene family, which belongs to the immunoglobulin supergene family, yet it displays restricted expression patterns and unique functions. Since the loss or reduced expression of BGP is associated with human colorectal carcinomas, the elements in its upstream regulatory region were analyzed. A cluster of transcriptional initiation sites and the minimal promoter, located within 150 bp upstream of the major transcriptional start site, were active in human colon carcinoma and hepatoma cells. Unlike the CEA gene, BGP gene transcription was not modulated by a silencer region; repetitive elements in the BGP upstream region were not involved in activation or repression. Footprinting experiments identified two cis-acting elements and mobility-shift assays demonstrated that these elements bound several transcription factors, among them, USF, HNF-4 and an AP-2-like factor. In cotransfection experiments, both the USF and HNF-4 transcription factors transactivate the RGP gene promoter and compete for the same regulatory element. The Spl transcription factor, shown to be involved in CEA gene transcriptional regulation, does not bind to the BGP gene promoter. We, therefore, propose that the relative distributions and interactions of these transcription factors mediate distinct transcriptional regulation of the BGP gene in colon and liver; this regulation could be distorted during the oncogenic process.

The Cea10 Gene Encodes A Secreted Member of the Murine Carcinoembryonic Antigen Family and is Expressed in the Placenta, Gastrointestinal Tract and Bone Marrow

“…AP-2 consensus sequences, like the one immediately upstream of the USF-binding motif of cealO and bgpl, have been postulated to convey epithelial cellspecific expression of E-cadherin and cytokeratin genes [51]. Therefore, it is conceivable that the Myc-related transcription factor USF, although ubiquitously expressed [42], can confer expression in epithelial cells in conjunction with AP-2 or AP-2-like factors, which have also been demonstrated to bind, but further upstream in the BGP promoter [49] in comparison to the concensus sequence found in ceal0.…”

Tumor-suppressive activity of CD66a in prostate cancer

“…[32][33][34] These genes do not contain TATA or CAAT boxes but do contain potential binding sites for basal and regulatory transcriptional elements. Using a gel-shift assay, Hauck et al 33 have shown that nuclear factors including upstream stimulatory factor, hepatic nuclear factor-4, and an activator protein-2-like molecule can bind to the human C-CAM promoter region. However, it is not clear whether these transcription factors are involved in the regulation of C-CAM gene expression during carcinogenesis.…”

CEACAM1, a SOX9 direct transcriptional target identified in the colon epithelium

“…The mechanisms regulating CEACAM1 expression are poorly understood and the transcription factors described to regulate its promoter are distinct between rat and human species (Hauck et al, 1994;Najjar et al, 1996). The previously described luciferase reporter containing the functional 3.1 kb CEACAM1 human promoter (Hauck et al, 1994) (p3.1sluc) was used to study the regulation by SOX9.…”