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 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 human IGF-I gene expression, and, in particular, on the intracellular factors that mediate IGF-I gene transcription. Toward this end the following five specific aims are proposed: 1. To dissect the functions of the two IGF-I gene promoters, to identify the structural elements required for basal gene transcription, and to clone and analyze the interacting transcriptional regulatory proteins. 2. To elucidate how a cyclic AMP-activated pathway stimulates IGF-I gene transcription and to identify the responsible regulatory factors. 3. To determine the molecular mechanisms by which the proto-oncogene c- myb activates IGF-I gene expression. 4. To determine whether IGF-I gene transcription is regulated by cell- cycle dependent mechanisms, and to define the steps by which the retinoblastoma gene product, pRb, inhibits IGF-I gene expression. 5. To clone and characterize the human homologues of growth hormone- regulated nuclear proteins that stimulate IGF-I gene transcription in the rat, and to elucidate their roles in human growth disorders.
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