We have continued to investigate 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 six IGFBPs. The IGFBPs determine the bioavailability of the IGFs and may inhibit or potentiate IGF action. As they have distinct properties and are differently regulated, the IGFBPs provide a flexible and versatile regulatory system. In the past year, we have studied the: (i) regulation of IGFBP-1 promoter activity in rat hepatoma cells by glucocorticoids and insulin; (ii) structure and regulation of the gene for the acid-labile subunit (ALS) of the 150 kDa IGFBP complex in plasma; (iii) formation of the 150 kDa ALS:IGFBP-3 complex in plasma; and (iv) binding of IGFBP-3 to human fibroblasts and rat glioma cells. Noteworthy results include: (i) Rat IGFBP-1 promoter. A glucocorticoid response element (GRE) and an insulin response (IRE) have been identified in the proximal region of the rat IGFBP-1 promoter that are essential for the stimulation of promoter activity by dexamethasone, and the rapid inhibition of promoter activity by insulin, respectively. Coordinated action of liver-enriched and hormonally regulated transcription factors binding to several sites is required for both basal and dexamethasone-stimulated promoter activity. (ii) Structure and regulation of the ALS gene. ALS mRNA is synthesized predominantly in liver, and regulated by growth hormone (GH). The mouse ALS gene contains a single intron. Constructs suitable for introducing an inactive ALS gene into the mouse genome by homologous recombination have been prepared. GH regulates ALS promoter activity in rat hepatoma cell line but not in GH-responsive mouse preadipocytes. (iii) Formation of plasma 150 kDa complexes, and release of IGF-I from the complexes by proteolysis of IGFBP-3. In addition to ternary complexes of ALS, IGFBP-3 and IGF-1, adult rat serum also contains 150 kDa binary complexes of ALS and proteolytically-nicked IGFBP-3 without bound IGF. We have shown that these complexes can form by direct associaation of ALS and IGFBP-3, and by proteolysis of IGFBP-3 within 150 kDa ternary complexes with subsequent release of IGF-1. Proteolysis of IGFBP-3 within 150 kDa complexes by cation-dependent serine proteases provides a mechanism by which IGFs can be mobilized from their reservior in the circulation. (iv) Binding of IGFBP-3 to human fibroblasts and rat glioma cells. Although IGFBP-3 binding to human fibroblasts and rat glioma cells is inhibited by heparin, IGFBP-3 does not bind to structurally similar heparan sulfate proteoglycans on the surface of these cells types.
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