Insulin-like growth factors I and II exert pleiotropic effects on diverse cell types, and have a broad range of functions in the embryo, fetus and adult. Although much evidence has accumulated supporting a major role for IGF-I as a post-natal growth factor, regulated at least in part by growth hormone, many studies have suggested a broader range of functions for this peptide, including actions on local tissue growth and on cell and tissue differentiation. These observations in turn imply that control of IGF-I synthesis may be on multi-factorial, responding not only to systemic hormonal signals but also to tissue- and developmentally- specific factors, and that regulation may occur at multiple levels, including gene transcription, RNA processing, and protein biosynthesis. As part of a long-term effort to understand the mechanisms by which IGF-I synthesis is controlled under different physiological conditions, the focus of this application will be on hormonal regulation of IGF-I gene expression, specifically on the signal transduction pathways and nuclear factors through which cyclic AMP and growth hormone stimulate IGF-I gene transcription. Toward this end the following four Specific Aims are proposed: 1. To define the mechanisms by which cyclic AMP activates the transcription factor, C/EBPdelta, and stimulates its nuclear translocation. 2. To determine how C/EBPdelta promotes IGF-I gene transcription. 3. To define the mechanisms by which growth hormone activates IGF-I gene transcription. 4. To characterize the nuclear proteins that bind to the IGF-I gene at the growth hormone-regulated DNAse I hypersensitive site, HS7.
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