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Mol Cell Biol, June 1998, p. 3483-3494, Vol. 18, No. 6
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Transactivation by Retinoid X Receptor-Peroxisome Proliferator-Activated Receptor gamma  (PPARgamma ) Heterodimers: Intermolecular Synergy Requires Only the PPARgamma Hormone-Dependent Activation Function

Ira G. Schulman,* Gang Shao, and Richard A. Heyman

Department of Retinoid Research, Ligand Pharmaceuticals, San Diego, California 92121

Received 4 November 1997/Returned for modification 11 December 1997/Accepted 20 March 1998

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  (PPARgamma ), 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 PPARgamma and RXR has a synergistic effect on the transactivation of reporter genes and on adipocyte differentiation in cultured cells. Mutation of the PPARgamma hormone-dependent activation domain (named tau c or AF-2) inhibits the ability of RXR-PPARgamma heterodimers to respond to ligands specific for either subunit. In contrast, the ability of RXR- and PPARgamma -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, PPARgamma , and modulates the activity of the heterodimer in a manner independent of the RXR hormone-dependent activation domain.

* Corresponding author. Mailing address: Department of Retinoid Research, Ligand Pharmaceuticals, 10255 Science Center Dr., San Diego, CA 92121. Phone: (619) 550-7214. Fax: (619) 550-7730. E-mail: ischulman{at}ligand.com.

Mol Cell Biol, June 1998, p. 3483-3494, Vol. 18, No. 6
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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