The overexpression of insulin receptor makes CHO cells resistant to the action of IGF-1: Role of IRS-1

We investigated the influence of the relative abundance of insulin and IGF-1 receptors on cellular growth, by measuring the stimulation of c-fos expression and of ³H-thymidine incorporation into DNA by insulin and IGF-1 in CHO cells overexpressing Insulin Receptor (CHO-IR). We found that CHO-IR cells were resistant to the action of IGF-1, but were more responsive to insulin, compared to parental clone. This result suggested the presence of a limiting step, distal to the IGF-1 receptor, in the transduction pathway. To address this question we measured the IGF-1 effect on c-fos expression in CHO-IR cells, transiently transfected with the cDNA for IRS-1, the common intracellular substrate for both insulin and IGF-1 receptors (CHO-IR/IRS-1 cells). In these cells IGF-1 stimulated a 10 fold higher c-fos expression compared to CHO-IR cells. These results suggest that the abundance of IRS-1, relative to the number of insulin and IGF-1 receptors, represents a limiting step for the intracellular transduction of insulin and IGF-1 biological messages.