HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 288/6/L1089    most recent 00352.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Wynes, M. W. Articles by Riches, D. W. H. Search for Related Content PubMed PubMed Citation Articles by Wynes, M. W. Articles by Riches, D. W. H.

Transcription of macrophage IGF-I exon 1 is positively regulated by the 5'-untranslated region and negatively regulated by the 5'-flanking region

¹Program in Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center; and ²Department of Immunology and ³Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado

Submitted 16 September 2004 ; accepted in final form 26 January 2005

Idiopathic pulmonary fibrosis (IPF) is an insidious lung disease with no known cure or effective therapy. Macrophage-derived insulin-like growth factor-I (IGF-I) is thought to play a role in the pathogenesis of IPF; however, little is known about the control of IGF-I expression in macrophages. In this report we investigated the cis-regulatory elements that control basal expression using luciferase reporter constructs in RAW 264.7 macrophages. We show that the +95 to +329 region contains elements necessary to direct maximal promoter activity, whereas the +251 to +329 region contains the minimal promoter. Mapping transcriptional start sites for endogenous IGF-I in primary macrophages revealed that the major transcriptional start site is centered at +150, whereas the most 3'-transcriptional start site is centered at +255. Nuclear proteins from primary and RAW 264.7 macrophages bind specifically to the region required for maximal promoter activity (+134 to +173) and to the region required for minimal promoter activity (+267 to +299). Antibody supershift assays indicate that Sp3 bound to the +267 to +299 region. Moreover, mutation of the putative binding site reduced Sp3 binding in EMSAs and increased promoter activity in luciferase reporter gene assays. We also found that the regions from –1711 to –855 and –855 to –337 contain putative macrophage-specific suppressor elements that do not function in HeLa or COS-7 epithelial cell lines. These data support the view that macrophage IGF-I expression is positively regulated by elements located in the 5'-untranslated region and negatively regulated by elements in the 5'-flanking region of the IGF-I gene.

gene regulation; lung; fibrosis; growth factor

This article has been cited by other articles:

				S. Sukhanov, Y. Higashi, S.-Y. Shai, C. Vaughn, J. Mohler, Y. Li, Y.-H. Song, J. Titterington, and P. Delafontaine IGF-1 Reduces Inflammatory Responses, Suppresses Oxidative Stress, and Decreases Atherosclerosis Progression in ApoE-Deficient Mice Arterioscler. Thromb. Vasc. Biol., December 1, 2007; 27(12): 2684 - 2690. [Abstract] [Full Text] [PDF]