A glycosylation-deficient endothelial cell mutant with modified responses to transforming growth factor-beta and other growth inhibitory cytokines: evidence for multiple growth inhibitory signal transduction pathways.
An endothelial cell line (M40) resistant to growth inhibition by transforming growth factor-beta type 1 (TGF beta 1) was isolated by chemical mutagenesis and growth in the presence of TGF beta 1. Like normal endothelial cells, this mutant is characterized by high expression of type II TGF beta receptor and low expression of type I TGF beta receptor. However, the mutant cells display a type II TGF beta receptor of reduced molecular weight as a result of a general defect in N-glycosylation of proteins. The alteration does not impair TGF beta 1 binding to cell surface receptors or the ability of TGF beta 1 to induce fibronectin or plasminogen activator inhibitor-type I production. M40 cells were also resistant to growth inhibition by tumor necrosis factor alpha (TNF alpha) and interleukin-1 alpha (IL-1 alpha) but were inhibited by interferon-gamma (IFN gamma) and heparin. These results imply that TGF beta 1, TNF alpha, and IL-1 alpha act through signal transducing pathways that are separate from pathways for IFN gamma and heparin. Basic fibroblast growth factor was still mitogenic for M40, further suggesting that TGF beta 1, TNF alpha, and IL-1 alpha act by direct inhibition of cell growth rather than by interfering with growth stimulatory pathways.
Medical Research Division, American Cyanamid, Pearl River, New York 10965.
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V
Fafeur
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B
O'Hara
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P
Böhlen
D000818:Animals; D002417:Cattle; D002455:Cell Division; D002460:Cell Line; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D006031:Glycosylation; D006131:Growth Inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D008562:Membrane Glycoproteins / Q000378:metabolism; D009154:Mutation; D011956:Receptors, Cell Surface / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014415:Tunicamycin / Q000494:pharmacology
D016326:Extracellular Matrix Proteins; D006131:Growth Inhibitors; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D014415:Tunicamycin