Insulin-like growth factors I and II comprise a structurally-related pair of circulating proteins of fundamental importance in mammalian growth and development. Although much evidence has accumulated supporting a major role for IGF-I as a postnatal growth factor, regulated at least in part by growth hormone, many studies suggest a broader range of functions for this peptide, including actions on fetal growth and on cell and tissue differentiation. These observations in turn imply that the control of IGF-I synthesis may be multifactorial, responding not only to 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 goal to understand the mechanisms by which IGF-I synthesis is controlled, the focus of this application will be on the regulation of IGF-I gene expression, and, in particular, on the signal transduction pathways and nuclear factors that mediate IGF-I gene transcription under different physiological and developmental conditions. Toward this end the following specific aims are proposed: 1. To determine the signaling pathways and molecular mechanisms by which growth hormone rapidly activates IGF-I gene transcription. 2. To define the mechanisms responsible for the stepwise induction of IGF- I gene expression during fetal and early postnatal development.
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