REGULATION OF INSULIN-LIKE GROWTH FACTOR I EXPRESSION

The goals of the investigation are to study the control of insulin-like
growth factor I (IGF I) biosynthesis in model cell culture systems and in
the whole animal. Based on our preliminary observations the human IGF I
gene gives rise by alternative RNA processing to two messenger RNA
transcripts encoding different peptide precursors. These initial studies
suggest that regulatory mechanisms controlling IGF I biogenesis include
both tissue-specific RNA splicing and tissue-specific protein processing.
The putative regulatory steps may be responsible for unique IGF I peptide
species subserving different roles as either hormones or
autocrine/paracrine growth stimulators. In order to study the regulation
of IGF I biosynthesis, I propose the following three specific objectives:
(1) To define the protein precursors, processing intermediates, and steps
leading to the secretion of mature IGF I by using the techniques of gene
transfer to introduce IGF I complementary DNAs (cDNAs) into hepatocyte and
fibroblast cell lines, and an inducible gene expression system to amplify
IGF I biosynthesis. (2) To determine by molecular cloning the structure
and sequence of rat IGF I messenger RNAs and gene. (3) To study the
regulation of IGF I gene expression during growth and development in the
rat using the homologous cDNAs and gene as probes, in particular to analyze
the role of growth hormone in enhancing IGF I biosynthesis.