Transcriptional regulation of the insulin-like growth factor-I receptor gene: evidence for protein kinase C-dependent and -independent pathways.

An important mechanism whereby growth factors stimulate vascular smooth muscle cell proliferation is by increasing insulin-like growth factor (IGF)-I receptor binding. To characterize the mechanisms involved, we studied transcription of the IGF-I receptor gene in rat aortic smooth muscle cells. Angiotensin II (100 nM) and basic fibroblast growth factor (5 ng/ml) caused a marked increase in IGF-I receptor messenger RNA (mRNA) levels, peaking at 3 h (215 +/- 16.8% and 85 +/- 7.4% above control, respectively). Nuclear run-on assays indicated that angiotensin II and fibroblast growth factor stimulated IGF-I receptor gene transcription by 2.1- and 2.5-fold, respectively. Down-regulation of protein kinase C, a serine/threonine kinase that is important in growth factor-activated signal transduction, completely inhibited fibroblast growth factor- but not angiotensin II-mediated up-regulation of IGF-I receptor mRNA. The protein kinase C inhibitors chelerythrine (3 microns), calphostin C (100 nM), and staurosporine (10 nM) also blocked fibroblast growth factor but not angiotensin II induction of IGF-I receptor mRNA. Thus, angiotensin II and fibroblast growth factor transcriptionally regulate the IGF-I receptor gene by protein kinase C-independent and -dependent pathways, respectively. In view of our prior data indicating that IGF-I receptor density is a critical determinant of vascular smooth muscle cell growth, our findings have particular relevance to understanding mechanisms whereby growth factors regulate vascular proliferation in vivo.