EXPRESSION OF MUTANT P21(RAS) 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, altho ugh the underlying inducing event has remained undefined. In order to address this matter, we have generated several immortalized human thyr oid epithelial cell lines containing a zinc-inducible mutant H-ras gen e and used these to investigate the relationship between expression of mutant p21(ras) and secretion of IGP-1. Induction of the transgene in the presence of zinc ions (Zn2+) was confirmed by Northern blot analy sis and immunocytochemistry. IGF-1 levels in serum-free medium, stripp ed of binding proteins, were monitored using a sensitive radioimmunoas say. Expression of mutant p21(ras) in these cells, induced by Zn2+, re sulted in an approximate 30-fold increase in the IGF-1 production rate , reaching a level exceeding that of human embryo fibroblasts. The dat a presented here suggest that an activating mutation of a ras oncogene may directly account for IGF-1 secretion in some human tumor cells.