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The PPAR2 A/B-Domain Plays a Gene-Specific Role in Transactivation and Cofactor Recruitment

Department of Biochemistry and Molecular Biology (A.B., L.G., M.M.A., S.M.), University of Southern Denmark, 5230 Odense M, Denmark; and Department of Clinical Biochemistry (R.B.), University Hospital of Copenhagen Rigshospitalet, 2100 Copenhagen, Denmark

Address all correspondence and requests for reprints to: Susanne Mandrup, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark. E-mail: s.mandrup{at}bmb.sdu.dk.

We have previously shown that adenoviral expression of peroxisome proliferator-activated receptors (PPARs) leads to rapid establishment of transcriptionally active complexes and activation of target gene expression within 5–8 h after transduction. Here we have used the adenoviral delivery system combined with expression array analysis to identify novel putative PPAR target genes in murine fibroblasts and to determine the role of the A/B-domain in PPAR-mediated transactivation of genomic target genes. Of the 257 genes found to be induced by PPAR2 expression, only 25 displayed A/B-domain dependency, i.e. significantly reduced induction in the cells expressing the truncated PPAR lacking the A/B-domain (PPARCDE). Nine of the 25 A/B-domain-dependent genes were involved in lipid storage, and in line with this, triglyceride accumulation was considerably decreased in the cells expressing PPARCDE compared with cells expressing full-length PPAR2. Using chromatin immunoprecipitation, we demonstrate that PPAR binding to genomic target sites and recruitment of the mediator component TRAP220/MED1/PBP/DRIP205 is not affected by the deletion of the A/B-domain. By contrast, the PPAR-mediated cAMP response element-binding protein (CREB)-binding protein (CBP) and p300 recruitment to A/B-domain-dependent target genes is compromised by deletion of the A/B-domain. These results indicate that the A/B-domain of PPAR2 is specifically involved in the recruitment or stabilization of CBP- and p300-containing cofactor complexes to a subset of target genes.

NURSA Molecule Pages Link:

Nuclear Receptors:   PR

Coregulators:   TRAP220  |  CBP  |  p300

Ligands:   GW 9662  |  Rosiglitazone