Mechanisms of insulin-like growth factor (IGF)-II-induced IGF-I receptor down-regulation in BC3H-1 muscle cells.
Muscle is an important target tissue for insulin-like growth factor (IGF) action. We have previously demonstrated that treatment of myoblasts with IGF-II decreased IGF-I receptor biosynthesis and steady-state mRNA levels. In addition, muscle cell differentiation was associated with a marked increase in the expression and secretion of IGF-II followed by similar down-regulation of the IGF-I receptor, suggesting an autocrine role for IGF-II in this process. To explore further the mechanisms by which IGF-II decreases IGF-I receptor expression in BC3H-1 muscle cells, dose-response studies of IGF-I and -II treatment on the amount of IGF-I receptor mRNA were carried out. In addition, to determine whether IGF-II decreases IGF-I receptor expression by stimulating receptor protein degradation, pulse/chase experiments with [35S]methionine/cysteine were carried out. Both IGF-I and -II induced significant down-regulation of IGF-I receptor mRNA. At low concentrations, IGF-I was more potent than IGF-II in inhibiting IGF-I receptor mRNA accumulation, suggesting that IGF-I receptor down-regulation induced by IGF-II is mediated principally through the IGF-I receptor in these cells. In addition, IGF-II decreased IGF-I receptor expression by stimulating receptor protein degradation as demonstrated by pulse/chase analysis of metabolically labelled receptors. Thus, IGF-II induces IGF-I receptor down-regulation in muscle cells through multiple mechanisms, including decreasing IGF-I receptor mRNA and stimulating IGF-I receptor protein degradation.
Department of Pediatrics, University of California, San Francisco 94143.
S M
SM
Rosenthal
E J
EJ
Brown
D000818:Animals; D015152:Blotting, Northern; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects*; D017403:In Situ Hybridization; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D007335:Insulin-Like Growth Factor II / Q000494:pharmacology*; D051379:Mice; D009132:Muscles / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D017526:Receptor, IGF Type 1 / Q000187:drug effects* / Q000235:genetics
D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1