GLYCOSYLTRANSFERASE ACTIVATION IN COLONIC ADENOCARCINOMA

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Dramatic changes in glycolipid metabolism associated with oncogenic transformation implicate a specific role for membrane glycolipids in regulation of cell growth and cellular recognition. These changes give rise to tumor specific membrane antigens which are useful diagnostically and as potential targets for immunotherapy. Although many examples of these tumor antigens have been documented, not much information is available relating to the mechanism of regulation of biosynthesis which prevents expression of these carbohydrate structures in normal cells and tissues and is activated to produce them in association with oncogenesis. A variety of lacto-series based carbohydrate antigens have been described to occur in human adenocarcinomas. Recent evidence has shown that activation of a normally unexpressed beta 1 leads to 3N-acetyl-glucosaminyltransferase required for lacto-series chain synthesis occurs in colonic epithelial cells and results in accumulation of these antigens. This application proposes to extend these observations to study in detail interactions of this and other enzyme activities associated with the synthesis of a variety of end-stage structures which occur in these tumors. The beta 1 leads to 3N- acetylglucosaminyltransferase which is activated in association with oncogenesis will be extensively studied. This activity will be characterized in adenocarcinoma cell lines, purified to homogeneity from a soluble source such as serum or milk and this enzyme studied in terms of its physical properties, antibodies will be prepared against it and these antibodies will be used in studies to isolate cDNA clones which encode the enzyme. This will then lead to studies of the regulation of gene expression during both development and oncogenesis. These studies will provide further information relating to the biochemical changes occurring in association with oncogenesis which gives rise to an important and potentially useful series of human tumor antigens, lacto-series based carbohydrate antigens.