Expression of mutant p21ras induces insulin-like growth factor 1 secretion in thyroid epithelial cells

There is substantial evidence supporting the existence of insulin-like growth factor 1 (IGF-1) autocrine circuits in many tumor types, although the underlying inducing event has remained undefined. In order to address this matter, we have generated several immortalized human thyroid epithelial cell lines containing a zinc-inducible mutant H-ras gene and used these to investigate the relationship between expression of mutant p21ras and secretion of IGF-1. Induction of the transgene in the presence of zinc ions (Zn2+) was confirmed by Northern blot analysis and immunocytochemistry. IGF-1 levels in serum-free medium, stripped of binding proteins, were monitored using a sensitive radioimmunoassay. Expression of mutant p21ras in these cells, induced by Zn2+, resulted in an approximate 30-fold increase in the IGF-1 production rate, reaching a level exceeding that of human embryo fibroblasts. The data presented here suggest that an activating mutation of a ras oncogene may directly account for IGF-1 secretion in some human tumor cells.