Insulin-like growth factor-1 (IGF-1), a conserved 70-residue secreted protein, plays a fundamental role in somatic growth in mammals and other vertebrate species. Although much evidence has accumulated supporting IGF-1 as a major postnatal growth factor, regulated by growth hormone (GH), many studies have suggested a broader range of functions for this peptide, including actions on local tissue growth, maintenance, and repair throughout the life span, as well as deleterious effects in cancer and aging. These observations in turn imply not only that control of IGF-1 synthesis may be multi-factorial, but also that each regulatory pathway may exert key critical actions on different aspects of growth, development, and disease. As part of a long-term effort to understand the mechanisms by which IGF-1 synthesis and action are controlled under different physiological conditions, the focus of the application will be on regulation of IGF-1 gene transcription by GH. Key goals will be to define the molecular mechanisms by which GH controls IGF-1 expression via the transcription factor, StatSb. Toward this end the following 4 Specific Aims are proposed: 1. To define the initial steps in activation of IGF-1 gene transcription by GH through StatSb. 2. To characterize mechanisms of termination of GH-stimulated IGF-1 transcription. 3. To determine if the HS7 region of the IGF-1 locus is both necessary and sufficient to mediate GH- regulated IGF-1 gene activation. 4. To characterize mechanisms of dysfunction of a natural amino acid substitution in human StatSb that is associated with profound growth failure. ? ? ?
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