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 a family of 6 IGFBPs. The IGFBPs provide a mechanism for the subtle and versatile regulation of IGF action. The IGFBPs determine the bioavailability of the IGFs and may inhibit or potentiate their actions. To better understand the biological role and mechanism of action of the IGFBPs, we have characterized the proteins, isolated cDNA and genomic clones, and studied the regulation of gene expression. (1) Hepatic IGFBP-1 transcription and IGFBP-1 mRNA levels are increased in streptozotocin- diabetic rats, and rapidly normalized following insulin treatment. Insulin also rapidly decreases IGFBP-1 transcription in H4-II-E rat hepatoma cells. Inhibition by insulin is dominant to stimulation by dexamethasone, cyclic AMP or phorbol esters. Ongoing protein synthesis is required for the rapid turnover of IGFBP-1 mRNA. (2) Both upstream and proximal sites are required for the efficient transcription of the TATA-less rat IGFBP-2 promoter. The proximal sites include 3 clustered GC boxes that bind Sp1 or closely related proteins, are sufficient to confer Sp1-induced promoter activity, and function synergistically to activate the promoter. (3) IGFBP-4 is the predominant IGFBP expressed by 3 bovine endothelial cell lines. Secreted IGFBP-r and IGFBP-4 mRNA are increased by agents that increase intracellular cyclic AMP in a clonal endothelial cell line established from bovine parathyroid. (4) IGFBP-6 purified from human cerebrospinal fluid and rat IGFBP-6 from the rat PC12 pheochromocytoma cell line are O-glycosylated. Enzymatic deglycosylation does not affect the marked preferential binding affinity of either ITFBP for IGF-II versus IGF-I. The binding specificities of IGFBP-6 and the other IGFBPs for a panel of recombinant IGF-II mutants were distinct, but more similar to each other than to the IGF-II/Mannose- 6-phosphate or IGF-I receptors.
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