Regulation of High Branching in N-linked Oligosaccharides

 The oligosaccharide moieties on glycoproteins are synthesized by the action of specific glycosyltransferases. A high degree of branching of N-linked oligosaccharides is frequently observed for the case of glycoproteins produced by cancer cells, and this can affect the biological nature of tumor cells (1), especially the metastatic potential (2,3). The formation of highly branched oligosaccharides is dependent on the up-regulation of a specific glycosyltransferase. In N-glycans, N-acetylglucosaminyltransferases III, IV, V and VI (GnTs-III, -IV, -V, and -VI) are responsible for the formation of the core structure on branching portions as described below, leading to changes in the entire oligosaccharide structure (4). N-Acetylglucosaminyltransferases I and II (GnTs-I and -II) play a key role in the synthesis of major oligosaccharides because knock-out mice of GnT-I are lethal. Sialyltransferase and fucosyltransferase are also important determinants of the terminal structures of oligosaccharides. However, GnTs-III, -IV, -V, and -VI play a pivotal role in high branching because they act in key reactions leading to branching. The gene expression of these glycosyltransferases are regulated in a tissue specific manner and post-translational regulation such as phosphorylation is sometimes involved in the activation of the glycosyltransferase. Although these GnTs recognize a common substrate, there is no homology in terms of cDNA sequence. In general, GnT-IV and -V promote high branching as well as the elongation of oligosaccharides while GnT-III serves to suppress them. GnT-IV is enhanced in chorionic carcinoma and GnT-V is related to tumor metastasis. The regulation of GnT-V activity is very complex. For example, activation by cell growth, a specific transcription factor such as the ets-family, stabilization of the mRNA by TGF beta treatment, etc. may be involved in its regulation. The oligosaccharide structures are not always determined by the level of glycosyltransferases. Once GnT-III acts on an oligosaccharide on glycoproteins, resulting in possible conformational changes of the sugar, GnT-V can no longer react with the oligosaccharides. By using this system, we were successful in inhibiting lung metastasis of mouse melanoma cells which had been transfected with the GnT-III gene. Recently, the cDNA of alpha1-6 fucosyltransferase (alpha1-6FucT) has been cloned (5). The oligosaccharide structure synthesized by alpha1-6FucT is useful for the differential diagnosis of hepatocellular carcinoma and in influencing the terminal structure of oligosaccharides. The overexpression of alpha1-6FucT in hepatoma cells suppresses experimental metastasis via alteration of oligosaccharide structures on adhesion molecules.
Eiji Miyoshi and Naoyuki Taniguchi
(Dept. Biochem., Osaka University Medical School)
References (1) Santer, UV, Gilbert, F, Glick, MC, Cancer Res. 44, 3730,1984
(2) Kobata, A, Eur. J. Biochem. 209, 483-501,1992
(3) Dennis,jw. Laferte, S. Waghorne, C. Breitman,ML. Kerbel,RS : beta 1-6 Branching of Asn-linked oligosaccaharides is directly associated with
metastasis. Science 236, 582, 1987
(4) Taniguchi, N, Miyoshi, E, Ko, JH, Ikeda, Y, Ihara, Y : Implication of N-acetylglucosaminyltransferases III and V in cancer : Gene regulation and signaling mechanism. Biochem. Biophys Acta, 1999 in press.
(5) Miyoshi, E, Noda, K, Yamaguchi, Y, Inoue, S, Ikeda, Y, Wang, W, Ko, JH, Uozumi, N, Li, W, Taniguchi, N : The alpha 1-6 fucosyltransferase gene and its biological significance. Biochem. Biophys Acta, 1999 in press.
Jun. 15, 1999

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