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J. Biol. Chem., Vol. 281, Issue 51, 39607-39619, December 22, 2006

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The Insulin-like Growth Factor-binding Protein 1 Gene Is a Primary Target of Peroxisome Proliferator-activated Receptors^*

Tatjana Degenhardt¹, Merja Matilainen¹, Karl-Heinz Herzig, Thomas W. Dunlop, and Carsten Carlberg^¶2

From the Department of Biochemistry and A.I. Virtanen Institute, University of Kuopio, FIN-70211 Kuopio, Finland and the ^¶Life Sciences Research Unit, University of Luxembourg, 162A, Avenue de la Faiencerie, Luxembourg L-1511, Luxembourg

Insulin-like growth factor-binding protein 1 (IGFBP-1) is a biomarker for metabolic and hyperproliferative diseases. At the same time, the nuclear receptors peroxisome proliferator-activated receptors (PPARs) are known for their critical role in the development of both the metabolic syndrome and various cancers. Here we demonstrate, in human hepatocellular carcinoma cells and in normal mouse liver, that IGFBP-1 mRNA expression is under the primary control of PPAR ligands. We applied an improved in silico screening approach for PPAR response elements (PPREs) and identified five candidate PPREs located within 10 kb of the transcription start site (TSS) of the IGFBP-1 gene. Chromatin immunoprecipitation assays showed that, in living cells, the genomic region containing the most proximal PPRE, at position -1200 (relative to the TSS), preferentially associates with multiple PPAR subtypes and various other components of the transcriptional apparatus, which include their heterodimerizing partner, retinoid X receptor, as well as phosphorylated RNA polymerase II, co-repressor, co-activator, and mediator proteins. Moreover, further chromatin immunoprecipitation assays demonstrated that the TSS regions of the IGFBP-1 gene and those of the related IGFBP-2, -5, and -6, but not of IGFBP-3 and -4 genes, bind PPARs as well. We also show that these additional PPAR binding genes contain a number of candidate PPREs and that their mRNA levels respond quickly to the presence of PPAR ligands, indicating that they are also primary PPAR target genes.

Received for publication, June 12, 2006 , and in revised form, October 24, 2006.

^* This work was supported by grants from the Academy of Finland, the Finnish Cancer Organisation, the Juselius Foundation, the Finnish Technology Agency (TEKES), and the European Union (Marie Curie RTN NucSys). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2 and Tables S1-S3.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Biochemistry, University of Kuopio, P. O. Box 1627, FIN-70211 Kuopio, Finland. Tel.: 358-17-163-062; Fax: 358-17-281-1510; E-mail: carlberg{at}messi.uku.fi.

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