We have extended our studies designed to understand how insulin-like growth factor binding proteins (IGFBPs) modulate the biological actions of IGF-I and IGF-II. The IGFs occur in plasma, other extracellular fluids, and tissues complexed to one or more members of the family of 6 IGFBPs. The IGFBPs determine the bioavailability of the IGFs, and may inhibit or potentiate their actions. A major determinant of the biological activity of the IGFBPs is its abundance in different tissues, which is determined in part by regulation of its synthesis. We have studied the regulation of IGFBP-2 transcription in rat liver by fasting, the regulation of IGFBP-1 transcription by insulin in diabetes and in rat hepatoma cells, and demonstrated that IGFBP-6 in human cerebrospinal fluid is O-glycosylated. (1) IGFBP-2 mRNA is increased in fasted rat liver (but not brain or kidney), and rapidly normalized by refeeding. Run-on transcription studies demonstrated a corresponding increase in the initiation of transcription of the IGFBP-2 gene. IGFBP-2 transcription and IGFBP-2 mRNA also are increased in neonatal rat liver. (2) Insulin rapidly inhibits IGFBP-1 transcription and IGFBP-1 mRNA in diabetic rat liver. Similarly, in H4-II- E rat hepatoma cells, insulin decreased IGFBP-1 transcription within 20 min. This is a direct effect of insulin, and is mediated by the insulin receptor. The H4-II-E cell line will be used to identify the insulin response elements in the IGFBP-1 promoter. (3) IGFBP-6, one of the predominant IGFBPs in human cerebrospinal fluid, was purified and shown to be O-glycosylated. Enzymatic deglycosylation did not alter its high, preferential affinity for IGF-II versus IGF-I. The effect of O-linked oligosaccharides on the localization of IGFBP-6 in tissues and its biological activity remain to be determined.
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