Insulin-like growth factor-I (IGF-I) and IGF-II are polypeptides that stimulate cell growth, survival or differentiation. In plasma and other extracellular fluids, they occur complexed to IGF-binding proteins (IGFBPs), a family of proteins that modulate their biological activity. The IGFBPs also may regulate cell growth independent of binding IGFs, providing a flexible and versatile system of cell regulation. We have studied the regulation of IGFBP gene expression and the biological activities of the IGFBPs. (i) Transcription of IGFBP-1 is dynamically regulated in response to metabolic and hormonal changes. Glucocorticoids increase and insulin inhibits IGFBP-1 promoter activity in a rat hepatoma cell line. Adjacent cis-elements in the proximal promoter are responsible for this regulation. Maximal stimulation of IGFBP-1 promoter activity by glucocorticoids requires synergistic interactions between the glucocorticoid receptor and the liver-enriched transcription factors, hepatocyte nuclear factor (HNF)-1 alpha and -beta. Studies to define the molecular mechanisms by which insulin inhibits IGFBP-1 promoter activity suggest that the signal transduction pathway includes phosphatidylinositol 3-phosphate kinase, protein kinase B/Akt, and possibly p70S6 kinase, and may involve regulation of the interaction of a member of the FKHR subfamily of HNF-3/forkhead transcription factors to the insulin response element. (ii) The main reservoir of IGFs is a 150- kilodalton complex in plasma that contains IGFBP-3 and an acid- labile subunit (ALS). Formation of this complex is dependent on the induction of ALS transcription by growth hormone (GH). GH induction of mouse ALS promoter activity in rat hepatoma cells is mediated by the binding of the transcription factors, STAT5a and STAT5b, to a single cis-regulatory element that resembles a gamma interferon activated sequence (GAS). (iii) Biologically active IGFs are released from the 150-kDa plasma complex by limited proteolysis of IGFBP-3 to form a fragment that has decreased binding affinity for the IGFs. Serine proteases and matrix metalloproteinase 3 (MMP-3) are responsible for the proteolysis of IGFBP-3 in serum from nonpregnant and pregnant adult rats, and neonatal rats. The serine protease may initiate the activation of latent MMP precursor, with activated MMP directly degrading IGFBP-3. (iv) IGFBP-3 inhibits DNA synthesis in mink lung epithelial cells independent of its ability to bind IGFs; IGF:IGFBP-3 complexes are not inhibitory. Studies are in progress to characterize the IGFBP-3 receptor that mediates growth inhibition, and to determine whether intact IGFBP-3 or a proteolytic fragment is responsible for the observed inhibition.
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