GENE-REGULATION BY IGF-I

Constitutive overexpression of the insulin-like growth factor-I (IGF-I) receptor makes 3T3 cells capable of growing in serum-free medium supplemented solely with IGF-I to the total exclusion of the platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) receptors, the other two receptors that are required for the growth of 3T3 cells. Pietrzkowski et al. (Cell Growth Differ 92:199-205, 1992) found that these cells, overexpressing the IGF-I receptor, can also be induced to grow by the addition of EGF. We have ascertained that the mechanism by which EGF induces growth in these cells is through the induction of substantial amounts of IGF-I RNA and IGF-I. In 3T3 cells overexpressing the EGF receptor, a functional IGF-I receptor is still required for growth. We have also found, using a temperature-sensitive mutant of the SV40 large T antigen, that the levels of IGF-I mRNA and of IGF-I secreted in the medium are markedly increased by a functional T antigen. Using an IGF-I promoter driving a reporter luciferase gene, we have determined that this increase in the expression of IGF-I by T-antigen occurs, at least in part, at a transcriptional level. It seems, therefore, that transformation by SV40 reduces the requirement for growth factors by increasing the production of IGF-I. (C) 1993 Wiley-Liss, Inc.