The primary objective of the proposal is to determine the roles of poly-N-acetyllactosamines in development, cell adhesion and cancer cell metastasis. In the past few years, we have made critical progress in this field. First, we have elucidated the biosynthetic pathways of poly-N-acetyllactosamines in both branched Nglycans and branched O-glycans. Second, we have cloned a cDNA encoding a novel beta1-Nacetylglucosaminyltransferase (beta3GIcNAcT-3) that forms extended core1 0-glycans and found that this enzyme belongs to the beta1,3-N-acetylglucosaminyltransferase gene family. Third, we have demonstrated that moderately increased expression of sialyl Lewis x dramatically increases metastatic capability of cancer cells. Based on these findings, three major areas of further studies are proposed as follows: 1) Identifying beta1, 3-N-acetylglucosaminyltransferases that play major roles in the biosynthesis of various poly-N-acetyllactosaminyl glycans. The studies will determine which beta3GIcNAcTs play a major role in adding poly-N-acetyllactosamines to N- or O-glycans. The studies will also determine if beta3GIcNAcT-2 and beta3GIcNAcT-7 form different products. 2) Determining the roles of beta3GIcNAcT-3 in cell adhesion. The studies will determine the roles of beta3GIcNAcT-3 by generating mutant mice with deficient 133GlcNAcT-3 and assess functional defects in leukocytes lacking beta3GIcNAcT-3. 3) Determine the roles of poly-N-acetyllactosamines in development and tumor formation, The studies will determine if the overexpression of beta3GIcNAcT-2 facilitates tumor formation while overexpression of beta3GIcNAcT-7 suppresses tumor formation. The studies will also determine if iGnT plays critical role in development and suppressing tumor formation through the gene knockout of iGnT and analysis of development and tumor formation in those mutant mice.
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