title: An inhibitor of O-glycosylation induces apoptosis in NIH3T3 cells and developing mouse embryonic mandibular tissues.
abstract: 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.
authors.affiliation: Biological Chemistry Section, NIDDK, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: E
authors.initials: E
authors.lastname: Tian
authors.forename: Kelly G
authors.initials: KG
authors.lastname: Ten Hagen
authors.forename: Lillian
authors.initials: L
authors.lastname: Shum
authors.forename: Howard C
authors.initials: HC
authors.lastname: Hang
authors.forename: Yoannis
authors.initials: Y
authors.lastname: Imbert
authors.forename: William W
authors.initials: WW
authors.lastname: Young
authors.forename: Carolyn R
authors.initials: CR
authors.lastname: Bertozzi
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Tabak
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006031:Glycosylation / Q000187:drug effects; D037102:Lectins / Q000378:metabolism; D008334:Mandible / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism; D051379:Mice; D017350:N-Acetylgalactosaminyltransferases / Q000037:antagonists & inhibitors*; D041681:NIH 3T3 Cells; D011748:Pyrogallol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014529:Uridine / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: C495991:1-68A compound; D004791:Enzyme Inhibitors; D037102:Lectins; D011748:Pyrogallol; D017350:N-Acetylgalactosaminyltransferases; D014529:Uridine