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J. Biol. Chem., Vol. 279, Issue 48, 50382-50390, November 26, 2004

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An Inhibitor of O-Glycosylation Induces Apoptosis in NIH3T3 Cells and Developing Mouse Embryonic Mandibular Tissues^*

E Tian, Kelly G. Ten Hagen, Lillian Shum¶, Howard C. Hang||, Yoannis Imbert**, William W. Young, Jr**, Carolyn R. Bertozzi||, and Lawrence A. Tabak¶¶

From the Biological Chemistry Section, NIDDK, National Institutes of Health, Bethesda, Maryland 20892, ^¶Cartilage Biology and Orthopaedics Branch, NIAMS, National Institutes of Health, Bethesda, Maryland 20892, ^||Department of Chemistry, University of California, Berkeley, California 94720-1460, ^**Department of Molecular, Cellular and Craniofacial Biology, School of Dentistry, and the Departments of Biochemistry and Molecular Biology and Pharmacology and Toxicology School of Medicine, University of Louisville, Louisville, Kentucky 40292, and the Departments of Chemistry and Molecular and Cell Biology and Howard Hughes Medical Institute, University of California, Berkeley, California 94720-1460

The family of UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferases (ppGaNTases) is responsible for initiating mucin-type O-linked glycosylation in higher eukaryotes. To begin to examine the biological role of O-linked glycosylation, mammalian cells were treated with a small molecule inhibitor (designated 1–68A, Ref. 15) of ppGaNTase activity. NIH3T3 cells exposed to the inhibitor were shown to undergo a significant reduction in cell surface O-glycosylation as detected by staining with jacalin and peanut agglutinin lectins after 30 min of treatment; no reduction in staining using antibodies to O-linked N-acetylglucosamine or the lectin concanavalin A was detected. Apoptosis was also observed in treated cells after 45 min of exposure, ostensibly following the O-glycosylation reduction. Overexpression of several different ppGaNTase isoforms restored cell surface O-glycosylation and rescued inhibitor-induced apoptosis. Additionally, mouse embryonic mandibular organ cultures exposed to 1–68A developed abnormally, presumably because of epithelial and mesenchymal apoptosis that followed a reduction in jacalin and peanut agglutinin staining. Our studies suggest that mucin-type O-linked glycosylation may be required for normal development and that ppGaNTases may play a role in the regulation of apoptosis.

Received for publication, June 8, 2004 , and in revised form, August 31, 2004.

^* This work was supported in part by National Institutes of Health Grant GM66047 (to C. R. B.) and EY015134 (to W. W. Y.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a National Institutes of Health Visiting Fellowship grant.

^¶¶ To whom correspondence should be addressed: NIDDK, National Institutes of Health, Bldg. 31, Rm. 2C39, 31 Center Dr., MSC 2290, Bethesda, MD 20892. Tel.: 301-496-3571; Fax: 301-402-2185; E-mail: tabakl{at}mail.nih.gov.

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