The primary object of the proposal is to determine the roles of poly-acetyllactosamines and trans Golgi network glycoprotein 46 which carries poly-N-acetyllactosamines in cancer cell adhesion, metastasis, and development. In the past few years, we have made critical progress in this field. First, we have demonstrated that moderate increased expression of sialyl LeX profoundly increases metastatic capability of cancer cells. Second, we have cloned a cDNA encoding b-1, 3 -N- acetylglucosaminyltransferase, iGnT, which is essential fo poly-N-acetyllactosamine synthesis.-Third, we have cloned nove forms of the trans-Golgi network glycoprotein, TGN46, which have homology with P-selectin ligand glycoprotein-1 in its extracellular domain. Based on these findings, four major areas of further studies are proposed as follows: 1) Determining the roles of iGnT in biosynthesis of various glycans. The studies will determine the role of iGnT in the synthesis of O-glycans, glycolipids and keratansulfate synthesis, elucidate the biosynthetic pathway of i and I antigens, and evaluate the roles of the transmembrane domain of iGnT for poly-N-acetyllactosamine synthesis. 2) Determining the roles of poly-N-acetyllactosamine in tumor formation. The studies will examine the expression of i and I antigens in tumors and determine if the acquisition or increase of polyN-acetyllactosamine, with or without sialyl LeX, leads into a transformed phenotype. 3) Determining the roles of poly-N-acetyllactosamine in development and cell-cell interaction. The studies will determine the roles of poly-N-acetyllactosamine in mouse development through knock-out of the iGnT gene and assess functional defects in leukocytes lacking iGnT. 4) Determining the roles of TGN46 in tumor formation. The studies will determine the roles of TGN46 in cell adhesion to selectins and in tumor formation, and evaluate TGN46 as a tumor marker.
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