Discrete roles for peroxisome proliferator-activated receptor γ and retinoid X receptor in recruiting nuclear receptor coactivators

Peroxisome proliferator-activated receptor gamma (PPAR gamma) plays a major role in adipogenesis. PPAR gamma binds to DNA as a heterodimer with retinoid X receptor (RXR), and PPAR gamma-RXR tan be activated by ligands specific for either receptor; the presence of both ligands can result in a cooperative effect on the transactivation of target genes. How these ligands mediate transactivation, however, remains unclear. PPAR gamma is known to interact with both the p160/SRC-1 family of coactivators and the distinct, multisubunit coactivator complex called DRIP. A single DRIP subunit, DRIP205 (TRAP220, PBP), binds directly to PPAR gamma. Here we report that PPAR gamma and RXR selectively interacted with DRIP205 and p160 proteins in a ligand-dependent manner. At physiological concentrations, RXR-specific ligands only induced p160 binding to RXR, and PPAR gamma-specific ligands exclusively recruited DRIP205 but not p160 coactivators to PPAR gamma. This selectivity was not observed in interaction assays off DNA, implying that the specificity of coactivator binding in response to ligand is strongly influenced by the allosteric effects of DNA-bound heterodimers. These coactivator-selective effects were also observed in transient-transfection assays in the presence of overexpressed p160 or DRIP coactivators. The results suggest that the cooperative effects of PPAR gamma- and RXR-specific ligands may occur at the level of selective coactivator recruitment.