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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK037449-08
Application #
2140094
Study Section
Endocrinology Study Section (END)
Project Start
1986-09-01
Project End
1995-03-31
Budget Start
1993-09-01
Budget End
1995-03-31
Support Year
8
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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

Showing the most recent 10 out of 44 publications