title: Examination of Ligand-Dependent Coactivator Recruitment by Peroxisome Proliferator-Activated Receptor-alpha (PPARalpha).
abstract: The ligand-dependent recruitment of coactivators to peroxisome proliferator-activated receptor-alpha (PPARalpha) was examined. PPAR-binding protein (PBP), PPARgamma coactivator-1alpha (PGC-1alpha), steroid receptor coactivator-1 (SRC-1), and CBP/p300-interacting transactivator with ED-rich tail 2 (CITED2) affected PPARalpha activity in the presence of Wy-14,643. The effects on PPARalpha activity in light of increased or decreased expression of these coactivators were qualitatively different depending on the ligand examined. Diminished expression of PGC-1alpha, SRC-1, or PBP by RNAi plasmids affected natural or synthetic agonist activity whereas only Wy-14,643 was affected by decreased PGC-1alpha. The interaction of PPARalpha with an LXXLL-containing peptide library showed ligand-specific patterns, indicative of differences in conformational change. The association of coactivators to PPARalpha occurs predominantly via the carboxyl-terminus and mutating (456)LHPLL to (456)LHPAA resulted in a dominant-negative construct. This research confirms that coactivator recruitment to PPARalpha is ligand-dependent and that selective receptor modulators (SRMs) of this important protein are likely.
authors.affiliation: Department of Veterinary and Biomedical Sciences and Center for Molecular Toxicology and Carcinogenesis, Pennsylvania State University, 201 Life Sciences Building, University Park, PA 16802, USA.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Tien
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Hannon
authors.forename: Jerry T
authors.initials: JT
authors.lastname: Thompson
authors.forename: John P
authors.initials: JP
authors.lastname: Vanden Heuvel