INSULIN-LIKE GROWTH-FACTOR (IGF) SUPPRESSION OF IGFBP-1 PRODUCTION - EVIDENCE FOR MEDIATION BY THE TYPE-I IGF RECEPTOR

The regulation of insulin-like growth factor binding protein-I (IGFBP- 1) by its ligands, IGF-I and IGF-II, was studied in continuous culture s of HepG2 human hepatoma cells. Both IGF-I and IGF-II in concentratio ns as low as 1-10 nmol/l caused significant suppression of IGFBP-1 pro tein levels. This suppression was accompanied by decreased IGFBP-1 mRN A levels occurring within 2-4 h of exposure to IGF-I or IGF-II, and by a significant decrease in IGFBP-1 promoter activity. IGF-I and IGF-II were equipotent in suppressing basal levels of IGFBP-1 protein, mRNA and promoter activity. IGF-I, IGF-II, and IGF-analogs with low IGFBP-1 affinity, (des 1-3)IGF-I and long R3IGF-I, all potently suppressed th e previously characterized increase in IGFBP-1 protein levels and prom oter activity induced by cAMP and theophylline. In contrast, [Leu-27]I GF-II, which interacts with the type II but not type I IGF receptor, h ad no effect on IGFBP-1 protein levels or promoter activity. Our data indicate that IGFBP-1 production is inhibited by its ligands, IGF-I an d IGF-II, and that this effect is probably mediated at the transcripti onal level. The effects of IGF-I and IGF-II apparently occur as a resu lt of binding to the type I IGF receptor, and are similar to the previ ously characterized suppressive effects of insulin on IGFBP-1 transcri ption mediated through the insulin receptor. When considered with prev ious data regarding expression of IGFBP-1 and the type I IGF receptor, our results suggest that IGF regulation of IGFBP-1 may play an as yet undefined role in fetal development and postnatal hepatic regeneratio n.