REGULATED SYNTHESIS OF SIALYLTRANSFERASES

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It is well established that correct glycosylation of glycoproteins and glycolipids is fundamental to normal development and maintenance of higher animals. However, little is known about the structural and functional relationship of the oligosaccharide chains and the regulation of their expression. Among the sugars that comprise the carbohydrate chains, sialic acid, present only as the terminal sugars, is perhaps the most extensively, albeit incompletely, studied. It is the long ranged goal of this project to elucidate the pathways that determine the tissue and development specificities of sialic acid moieties on glycoconjugates. At least five, and most likely more, sialytransferases are required in the biosynthesis of the major sialic acid linkages found in mammalian glycoproteins. However, previous analysis of the functionality of sialic acids and the regulated expression of sialytransferases has been hampered by lack of sequence information from which specific molecular probes can be constructed. Efforts from this and other laboratories resulted in the sequence elucidation of the hepatic beta-galactoside alpha2,6- sialytransferase mRNA is modulated via the glucocorticoid pathway. Current observations from this laboratory has also uncovered a family of transcripts closely related to the hepatic alpha2,6-sialytransferase mRNA and exhibit a tissue specific pattern of expression. At least on of these related transcripts putatively encodes a divergent polypeptide sequence. An immediate objective of this study is a detailed characterization of the different members of this family and an assessment of the relationship and genetic origin of the individual transcripts. Subsequently, the functionality as well as in vivo and in vitro patterns of synthesis of these transcripts and polypeptides will be addressed. A parallel goal of this study is the elucidation of regulatory pathways that govern the expression of this family of sialytransferase related transcripts. To this end, requisite regulatory sequences will be identified and tested by the expression of chimeric constructs.