Ligand type-specific Interactions of Peroxisome Proliferator-activated Receptor γ with Transcriptional Coactivators*

Abstract

The nuclear peroxisome proliferator-activated receptor γ (PPARγ) is a member of the nuclear receptor superfamily and acts as a ligand-dependent transcription factor mediating adipocyte differentiation, cell proliferation and inflammatory processes, and modulation of insulin sensitivity. Members of the 160-kDa protein (SRC-1/TIF2/AIB-1) family of coactivators, CBP/p300 and TRAP220/DRIP205, are shown to interact directly with PPARγ and potentiate nuclear receptor transactivation function in a ligand-dependent fashion. Because PPARγ ligands exert partially overlapping but distinct subsets of biological action through PPARγ binding, we wished to examine whether interactions between PPARγ and known coactivators were induced to the same extent by different classes of PPARγ ligand. The natural ligand 15-deoxy-Δ12,14-prostaglandin J₂ induced PPARγ interactions with all coactivators tested (SRC-1, TIF2, AIB-1, p300, TRAP220/DRIP205) in yeast and mammalian two-hybrid assays, as well as in a glutathione S-transferase pull-down assay. However, under the same conditions troglitazone, a synthetic PPARγ ligand that acts as an antidiabetic agent, did not induce PPARγ interactions with any of the coactivators. Our findings suggest that ligand binding may alter PPARγ structure in a ligand type-specific way, resulting in distinct PPARγ-coactivator interactions.