Research Project
3271497
A possible functional role of cell-surface glycoconjugates in the mutual recognition of cell surfaces during development and differentiation has often been discussed, yet no solid data have been provided for a realistic mechanism. Among various carbohydrates showing stage-specific expression during embryogenesis, two types of structures, the fucosylated type 2 chains and the extended globo-series, are the basic, most commonly expressed antigens at certain stages of development in both mouse and man. The possibility that these structures may play important roles in cell recognition has been supported by the fact that multimeric oligosaccharides linked to lysyllysine can inhibit "compaction" of morula and induce decompaction. On the other hand, our studies and others indicate that affinity-purified polyclonal and monoclonal antibodies to GM3, GM1, GD3, and Gg3 inhibit cell proliferation and expression of various phenotypes characteristic of tumor cells, and modify development or differentiation. Based on these findings, we propose to study: (1) The basic mechanism of the change of carbohydrate structure in teratocarcinoma cells as a model of differentiation associated with embryogenesis. Two key glycosyltransferases, GDP-Fuc:nLc4/nLc6 Alpha1-3Fuc transferase (for synthesis of Le-x) and UDP-Gal:Gb4 Beta1-3Gal transferase, and their genes will be isolated. (2) The functional significance of such carbohydrate changes, particularly those of mono-, di-, and trimeric Le-x, Le-Y, Ii, and extended globo-series antigens, in the process of cell recognition. (3) The isolation and characterization of recognition proteins, which could be directed to those stage-specific carbohydrates during development and differentiation. (4) Anti-glycolipid antibody-dependent growth inhibition of "normal" cells in vitro and its mechanism. (5) Anti-glycolipid antibody-dependent modification of development.
