Transactivation by retinoid X receptor peroxisome proliferator-activated receptor γ (PPARγ) heterodimers:: Intermolecular synergy requires only the PPARγ hormone-dependent activation function

The ability of DNA sequence-specific transcription factors to synergistically activate transcription is a common property of genes transcribed by RNA polymerase II. The present work characterizes a unique form of intermolecular transcriptional synergy between two members of the nuclear hormone receptor superfamily, Heterodimers formed between peroxisome proliferator-activated receptor gamma (PPAR gamma), an adipocyte-enriched member of the superfamily required for adipogenesis, and retinoid X receptors (RXRs) can activate transcription in response to ligands specific for either subunit of the dimer, Simultaneous treatment with ligands specific for both PPAR gamma and RXR has a synergistic effect on the transactivation of reporter genes and on adipocyte differentiation in cultured cells. Mutation of the PPAR gamma hormone-dependent activation domain (named tau c or AF-2) inhibits the ability of RXR-PPAR gamma heterodimers to respond to ligands specific for either subunit, In contrast, the ability of RXR- and PPAR gamma-specific ligands to synergize does not require the hormone-dependent activation domain of RXR, The results of in vitro and in vivo experiments indicate that binding of ligands to RXR alters the conformation of the dimerization partner, PPAR gamma, and modulates the activity of the heterodimer in a manner independent of the RXR hormone-dependent activation domain.