OPTIMAL RATIOS OF BILIARY GLYCOPROTEIN ISOFORMS REQUIRED FOR INHIBITION OF COLONIC TUMOR-CELL GROWTH

Rodent biliary glycoprotein (Bgp), also known as C-CAM, has recently b een shown to function as a tumor suppressor in colon, prostate, and bl adder cancers. This glycoprotein is a member of the carcinoembryonic a ntigen family and is one of the only proteins in this family to encode either a long (71-73 amino acids) or short (10 amino acids) cytoplasm ic domain. We and others have shown that the growth-inhibitory propert ies of Bgp depend upon the expression of its long cytoplasmic domain. However, the two Bgp isoforms normally coexist in most cell types surv eyed; the longer variant is usually present in lower amounts than the shorter one. In this study, we have examined the in vitro and in vivo growth properties of both mouse Bgp variants separately and in combina tion. To determine the physiologically relevant expression levels and ratios of the two Bgp variants, we have quantified the amount of the l onger variant in normal colonic epithelial cells and showed that it co nstitutes 15-20% of total Bgp expressed in this tissue. To mimic the i n vivo situation, we have generated double transfectant cell lines exp ressing the longer and shorter Bgp isoforms coordinately in tumorigeni c CT51 mouse colonic carcinoma cells and demonstrated that the longer Bgp isoform exhibits a dominant tumor growth inhibition phenotype over that of the shorter variant within physiological levels of expression of Bgp. Unexpectedly, significant overexpression of the longer Bgp is oform alone led to reversal of the tumor inhibition phenotype. These r esults, therefore, suggest that there may be a limiting threshold of B gp expression or Bgp-associating proteins mediating the tumor inhibiti on phenotype.