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 tissue 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 six IGFBPs provide a flexible and versatile regulatory system. The two thrusts of our program in the past year have been: (i) the transcriptional regulation of the rat IGFBP-1 and IGFBP-2 genes, because the synthesis and abundance of these proteins is largely regulated at the transcriptional level; and (ii) the biological actions of IGFBPs on target cells, using recombinant IGFBP-6. Noteworthy results include: (i) IGFBP-1 promoter. A region has been identified in the proximal promoter that determines the stimulation of promoter activity by cyclic AMP and phorbol esters. In addition, a glucocorticoid response element and an insulin response element have been identified and shown to be essential for the stimulation of promoter activity by dexamethasone, and the rapid inhibition of promoter activity by insulin, respectively. Present efforts are directed toward identifying the transcription factor that binds to the insulin response element, and the signal transduction pathway by which insulin regulates IGFBP-1 transcription. (ii) IGFBP-2 promoter. The IGFBP-2 promoter is GC-rich, but lacks TATA and initiator sequences. Three clustered Sp1 sites in the proximal promoter are critical for basal promoter activity in BRL-3A rat liver cells. We are presently trying to determine the relative contributions of the SP1 sites and of secondary structure in the proximal promoter region to the choice of a precise transcription initiation site. (iii) Biological actions of IGFBPs on target tissues. We have expressed recombinant human IGFBP-6. Like native IGFBP-6, recombinant human IGFBP- 6 is O-glycosylated and has 50-fold greater affinity for IGF-II than IGF- I. Incubation of L6A1 rat myoblasts with recombinant IGFBP-6 inhibited IGF-II-mediated myoblast differentiation. The added IGFBP-6 remains in the culture medium, and does not associate with the cell surface or extracellular matrix. Our results are consistent with the hypothesis that pericellular localization is required for IGF-II: IGFBP-6 complexes to be biologically active. Mutants will be introduced into IGFBP-6 to alter its localization to determine if potentiation of biological activity will result.
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| Hammoud, Ahmad; Carrell, Douglas T; Meikle, A Wayne et al. (2010) An aromatase polymorphism modulates the relationship between weight and estradiol levels in obese men. Fertil Steril 94:1734-8 |
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