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 inhuman colonic adenocarcinomas. Recent evidence has shown that activation of a normally unexpressed beta1-leads to 3N- acetylglucosaminyltransferase 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 other enzyme activities associated with the synthesis of a variety of end-stage structures which occur in these tumors. The beta1-3N-acetylglucosaminyltransferase which is activated is association with oncogenesis will be extensively studied. This enzyme will be purified to homogeneity from a soluble enzyme source such as serum or milk, antibodies prepared against it, and this enzyme studied in terms of its physical properties. N- terminal sequence data will be obtained which, along with specific antibodies, will form a basis for future studies relating to isolation of genetic information which encodes the enzyme. This will then lead to studies of the regulation of gene expression during both development and oncogenesis. Coupled with this will be studies of the basis for relative synthesis of type 1 or 2 chain structures in normal mucosa and adenocarcinoma tumors. The beta1 leads to 3 galactosyltransferase associated with type 1 chain synthesis will also be studied extensively as an isolated protein and in terms of membrane interactions with other components in order to gain information on the detailed basis for almost exclusive synthesis of type 1 chain structures in normal mucosa as compared to tumors which contain a high proportion of type 2 chain based structures.
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