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.
Du
J
J
Department of Medicine, Emory University, Atlanta, Georgia 30322, USA.
Meng
X P
XP
Delafontaine
P
P
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005786:Gene Expression Regulation; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D009124:Muscle Proteins / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017451:Receptors, Somatomedin / Q000235:genetics*; D014158:Transcription, Genetic
D009124:Muscle Proteins; D012333:RNA, Messenger; D017451:Receptors, Somatomedin; D016222:Fibroblast Growth Factor 2; D000804:Angiotensin II; D015240:Phorbol 12,13-Dibutyrate; D007334:Insulin-Like Growth Factor I; D011493:Protein Kinase C