Control of insulin-like growth factor (IGF) action by regulation of IGF-I receptor expression

The insulin-like growth factors (IGFs) control many aspects of growth, development and differentiation, and aberrant IGF action is implicated in a number of pathological states. Most of the actions of both IGF-I and IGF-II are mediated by their activation of the IGF-I receptor, a transmembrane tyrosine kinase that is structurally and functionally related to the insulin receptor. Control of the IGF-I receptor number at the cell surface is an important level at which IGF action can be regulated. Cell-surface receptor number, in turn, is principally determined by the level of expression of the IGF-I receptor gene. An important transcriptional regulatory factor that appears to be responsible for controlling IGF-I receptor gene expression is the product of the WT1 Wilms tumor suppressor gene. This latter protein functions by binding to specific sequences in the IGF-I receptor promoter and repressing transcription. During normal renal development, increased expression of the WT1 gene leads to repression of IGF-I receptor gene expression, allowing differentiation of the metanephrogenic blastema into renal epithelium. Persistent receptor expression due to mutational loss of WT1 function may contribute to the etiology of Wilms tumor. Decreased WT1 expression and subsequent up-regulation of the IGF-I receptor has also been implicated in non-malignant proliferative disorders such as benign prostatic hyperplasia.