Ligand type-specific interactions of peroxisome proliferator-activated receptor gamma with transcriptional coactivators

The nuclear peroxisome proliferator-activated receptor gamma (PPAR gamma) i s a member of the nuclear receptor superfamily and acts as a ligand-depende nt transcription factor mediating adipocyte differentiation, cell prolifera tion and inflammatory processes, and modulation of insulin sensitivity. Mem bers of the 160-kDa protein (SRC-1/TIF2/AIB-1) family of coactivators, CBP/ p300 and TRAP220/DRIP205, are shown to interact directly with PPAR gamma an d potentiate nuclear receptor transactivation function in a ligand-dependen t fashion. Because PPAR gamma ligands exert partially overlapping but disti nct subsets of biological action through PPAR gamma binding, we wished to e xamine whether interactions between PPAR gamma and known coactivators were induced to the same extent by different classes of PPAR gamma ligand. The n atural ligand 15-deoxy-Delta 12,14-prostaglandin J(2) induced PPAR gamma in teractions with all coactivators tested (SRC-1, TIF2, AIB-1, p300, TRAP220/ DRIP205) in yeast and mammalian two-hybrid assays, as well as in a glutathi one S-transferase pull-down assay. However, under the same conditions trogl itazone, a synthetic PPAR gamma ligand that acts as an antidiabetic agent, did not induce PPAR gamma interactions with any of the coactivators. Our fi ndings suggest that ligand binding may alter PPAR gamma structure in a liga nd type-specific way, resulting in distinct PPAR gamma -coactivator interac tions.