Insulin-like growth factor (IGF) suppression of IGFBP-1 production: evidence for mediation by the type I IGF receptor.
The regulation of insulin-like growth factor binding protein-1 (IGFBP-1) by its ligands, IGF-I and IGF-II, was studied in continuous cultures of HepG2 human hepatoma cells. Both IGF-I and IGF-II in concentrations as low as 1-10 nmol/l caused significant suppression of IGFBP-I protein levels. This suppression was accompanied by decreased IGFBP-1 mRNA levels occurring within 2-4 h of exposure to IGF-I or IGF-II, and by a significant decrease in IGFBP-1 promoter activity. IGF-I and IGF-II were equipotent in suppressing basal levels of IGFBP-1 protein, mRNA and promoter activity. IGF-I, IGF-II, and IGF-analogs with low IGFBP-1 affinity, (des 1-3)IGF-I and long R3IGF-I, all potently suppressed the previously characterized increase in IGFBP-1 protein levels and promoter activity induced by cAMP and theophylline. In contrast, [Leu-27]IGF-II, which interacts with the type II but not type I IGF receptor, had no effect on IGFBP-1 protein levels or promoter activity. Our data indicate that IGFBP-1 production is inhibited by its ligands, IGF-I and IGF-II, and that this effect is probably mediated at the transcriptional level. The effects of IGF-I and IGF-II apparently occur as a result of binding to the type I IGF receptor, and are similar to the previously characterized suppressive effects of insulin on IGFBP-1 transcription mediated through the insulin receptor. When considered with previous data regarding expression of IGFBP-1 and the type I IGF receptor, our results suggest that IGF regulation of IGFBP-1 may play an as yet undefined role in fetal development and postnatal hepatic regeneration.
Lee
P D
PD
Department of Pediatrics, Baylor College of Medicine, Houston, TX.
Suwanichkul
A
A
DePaolis
L A
LA
Snuggs
M B
MB
Morris
S L
SL
Powell
D R
DR
D015152:Blotting, Northern; D006528:Carcinoma, Hepatocellular; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D002460:Cell Line; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1; D007335:Insulin-Like Growth Factor II / Q000494:pharmacology*; D007700:Kinetics; D008113:Liver Neoplasms; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D014407:Tumor Cells, Cultured
D002352:Carrier Proteins; D018970:Insulin-Like Growth Factor Binding Protein 1; D012333:RNA, Messenger; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1