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Regulation of Insulin-Like Growth Factor I Bioavailability in Growing Animals¹

Department of Cellular Physiology, Babraham Institute, Cambridge CB2 4AT, United Kingdom

Abstract

Insulin-like growth factor I (IGF-I) bioavailability is due to two regulatory stages: its biosynthesis and the subsequent modulation of its activity and susceptibility to degradation by IGF binding proteins (IGFBPs). Synthesis of IGF-I is ubiquitous, but the liver is its major site of synthesis and is thought to be responsible for most IGF-I found in the circulation; this allows both tissue-specific and coordinated actions of IGF-I. The IGF-I gene is complex, consisting of six exons, the mature peptide being encoded by parts of exons 3 and 4; four mRNA species can be derived from the gene by alternate splicing of exons 1 or 2 and 5 or 6. We have demonstrated a differential sensitivity of transcript abundance to GH and nutritional status in normal animals treated in physiological conditions, with exon 2-derived mRNA being more responsive than exon 1-derived mRNA; such relationships were not found for exons 5 and 6. The significance of these findings is not clear at present but could relate to the regulation of IGF-I gene transcription, mRNA stability, translatability of the different transcripts, or to some function of the encoded proteins. After it is synthesized, practically all IGF-I is associated with one of a family of at least six highly specific IGFBPs. These function to protect IGF-I from degradation, to transport it to specific sites, and to modulate (inhibit or potentiate) IGF-I activity. Because no conventional stores of IGF-I exist, IGFBP, and particularly IGFBP-3 as a ternary complex, provide a circulating reservoir of IGF-I. We have investigated the function of the high molecular weight IGFBP in the circulation using an anti-IGF-I antiserum and have demonstrated that circulating reservoir IGF-I can exert important effects on IGF-I bioactivity.

Key Words: Insulin-like Growth Factor I • Alternate Splicing • mRNA • Binding Proteins • Antibody • Growth Hormone • Nutritional Status

¹ I am grateful for the scientific skills of and many discussions with the following: Helen Flick-Smith, Claire Stewart, Rod Hill, Andrew Lemmey, Jonah Jones, Ted Saunders, Jon Lyall, and Stewart Gilmour. Part of this work falls within the scope of International Patent Application PCT/GB93/01774.