title: The insulin-like growth factor-binding protein 1 gene is a primary target of peroxisome proliferator-activated receptors.
abstract: 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.
authors.affiliation: Department of Biochemistry and A.I. Virtanen Institute, University of Kuopio, FIN-70211 Kuopio, Finland.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Degenhardt
authors.forename: Merja
authors.initials: M
authors.lastname: Matilainen
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Herzig
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Dunlop
authors.forename: Carsten
authors.initials: C
authors.lastname: Carlberg
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D008099:Liver / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D008957:Models, Genetic; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism*; D011485:Protein Binding; D012319:RNA Polymerase II / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D018970:Insulin-Like Growth Factor Binding Protein 1; D008024:Ligands; D047492:Peroxisome Proliferator-Activated Receptors; D012333:RNA, Messenger; D012319:RNA Polymerase II