The somatomedins or insulin-like growth factors (IGF-I and II) comprise a family of circulating peptides which share both structural and functional similarities with each other and with insulin. Although much evidence has accumulated supporting a role for IGF-I as a major mammalian postnatal growth factor, regulated at least n part by growth hormone, recent studies suggest a broader range of functions for this peptide, including actions on local growth processes and in cell and tissue differentiation. These observations i turn imply that the control of IGF-I biosynthesis may be multifactorial, responding not only to hormones but also to tissue and developmentally-specific factors, and that regulation may occur at multiple levels, including gene transcription, RNA processing, and protein translation. As part of a long-term goal to define the mechanisms by which IGF-I gene expression, and ultimately IGE-I synthesis is modulated both in the whole organism and in representative model systems, the focus of this application will be on the structural aspects of the IGF-I gene and its mRNAs which contribute to multifactorial regulation under different physiological conditions. In this context five specific aims are proposed: 1. To define by molecular cloning and DNA sequencing all the mRNA species that result from transcription and processing of the rat IGF-I gene. 2. To characterize the entire rat IGF-I gene, including its promoter and regulatory regions. 3. To dissect the functions of the rat IGF-I gene promoter, in particular to define the elements required for regulation by growth hormone, and to determine the mechanisms by which growth hormone activates IGF-I gene transcription. 4. To determine under physiological conditions whether modulation of IGF-I gene expression occurs primarily via transcriptional mechanisms, or whether alternative RNA splicing also is a regulated process. 5. To define the contribution of translational regulation to the control of IGF-I biosynthesis, in particular to examine the role of the long 5' untranslated region of IGF-I mRNAs in modifying the rate of peptide synthesis.
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