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 (TGFbeta1) was isolated by chemical mutagenesis and growth in the presence of TGFbeta1. Like normal endothelial cells, this mutant is characterized by high expression of type II TGFbeta receptor and low expression of type I TGFbeta receptor. However, the mutant cells display a type II TGFbeta receptor of reduced molecular weight as a result of a general defect in N-glycosylation of proteins. The alteration does not impair TGFbeta1 binding to cell surface receptors or the ability of TGFbeta1 to induce fibronectin or plasminogen activator inhibitor-type I production. M40 cells were also resistant to growth inhibition by tumor necrosis factor alpha (TNFalpha) and interleukin-1 alpha (IL-1alpha) but were inhibited by interferon-gamma (IFNgamma) and heparin. These results imply that TGFbeta1, TNFalpha, and IL-1alpha act through signal transducing pathways that are separate from pathways for IFNgamma and heparin. Basic fibroblast growth factor was still mitogenic for M40, further suggesting that TGFbeta1, TNFalpha, and IL-1alpha act by direct inhibition of cell growth rather than by interfering with growth stimulatory pathways.