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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Endocrinology Study Section (END)
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Washington University
Schools of Medicine
Saint Louis
United States
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Woelfle, Joachim; Rotwein, Peter (2004) In vivo regulation of growth hormone-stimulated gene transcription by STAT5b. Am J Physiol Endocrinol Metab 286:E393-401
Woelfle, Joachim; Billiard, Julia; Rotwein, Peter (2003) Acute control of insulin-like growth factor-I gene transcription by growth hormone through Stat5b. J Biol Chem 278:22696-702
Billiard, J; Umayahara, Y; Wiren, K et al. (2001) Regulated nuclear-cytoplasmic localization of CCAAT/enhancer-binding protein delta in osteoblasts. J Biol Chem 276:15354-61
Billiard, J; Grewal, S S; Lukaesko, L et al. (2001) Hormonal control of insulin-like growth factor I gene transcription in human osteoblasts: dual actions of cAMP-dependent protein kinase on CCAAT/enhancer-binding protein delta. J Biol Chem 276:31238-46
Umayahara, Y; Billiard, J; Ji, C et al. (1999) CCAAT/enhancer-binding protein delta is a critical regulator of insulin-like growth factor-I gene transcription in osteoblasts. J Biol Chem 274:10609-17
Le Stunff, C; Rotwein, P (1998) Growth hormone stimulates interferon regulatory factor-1 gene expression in the liver. Endocrinology 139:859-66
Umayahara, Y; Ji, C; Centrella, M et al. (1997) CCAAT/enhancer-binding protein delta activates insulin-like growth factor-I gene transcription in osteoblasts. Identification of a novel cyclic AMP signaling pathway in bone. J Biol Chem 272:31793-800
Ye, P; Umayahara, Y; Ritter, D et al. (1997) Regulation of insulin-like growth factor I (IGF-I) gene expression in brain of transgenic mice expressing an IGF-I-luciferase fusion gene. Endocrinology 138:5466-75
McCarthy, T L; Ji, C; Shu, H et al. (1997) 17beta-estradiol potently suppresses cAMP-induced insulin-like growth factor-I gene activation in primary rat osteoblast cultures. J Biol Chem 272:18132-9
Bui, T; Kuo, C; Rotwein, P et al. (1997) Prostaglandin A2 specifically represses insulin-like growth factor-I gene expression in C6 rat glioma cells. Endocrinology 138:985-93

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