Stimulatory effect of PDGF on HMG-CoA reductase activity and N-linked glycosylation contributes to increased expression of IGF-1 receptors in human fibroblasts.
In the present paper, we show that the prereplicative period in platelet-derived growth factor (PDGF)-stimulated human diploid fibroblasts (HDF) includes an early increase in 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity followed by an increased N-linked glycosylation. HMG-CoA reductase inhibitors abolished these events and also prevented progression of cells into S-phase, indicating that mevalonate (MVA)-dependent glycosylation might be required in PDGF-mediated cell growth. Furthermore, PDGF was demonstrated to increase the number of insulin-like growth factor 1 (IGF-1) binding sites in HDF. This event, which was dependent on MVA, took place late in the prereplicative period and was corrected to a significant increase in the expression of de novo synthesized IGF-1 receptor (IGF-1R) proteins at the cell membrane. The PDGF-induced IGF-1R expression was suppressed in the presence of tunicamycin, an inhibitor of N-linked glycosylation. Taken together, our findings suggest an important role of MVA and N-linked glycosylation in PDGF-mediated growth activation of HDF.
Carlberg
M
M
Department of Tumor Pathology, Karolinska Institutet, Stockholm, Sweden.
Larsson
O
O
D002455:Cell Division; D004247:DNA / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D005944:Glucosamine / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007223:Infant; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008148:Lovastatin / Q000494:pharmacology; D008297:Male; D008798:Mevalonic Acid; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis*; D016196:S Phase
D004791:Enzyme Inhibitors; D006888:Hydroxycholesterols; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010982:Platelet-Derived Growth Factor; D007334:Insulin-Like Growth Factor I; C007997:25-hydroxycholesterol; D004247:DNA; D008148:Lovastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D017526:Receptor, IGF Type 1; D005944:Glucosamine; D008798:Mevalonic Acid