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Molecular and Cellular Biology, November 2000, p. 8008-8017, Vol. 20, No. 21
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Discrete Roles for Peroxisome Proliferator-Activated Receptor gamma  and Retinoid X Receptor in Recruiting Nuclear Receptor Coactivators

Wen Yang, Christophe Rachez, and Leonard P. Freedman*

Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021

Received 2 May 2000/Returned for modification 22 June 2000/Accepted 31 July 2000

Peroxisome proliferator-activated receptor gamma  (PPARgamma ) plays a major role in adipogenesis. PPARgamma binds to DNA as a heterodimer with retinoid X receptor (RXR), and PPARgamma -RXR can 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. PPARgamma 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 PPARgamma . Here we report that PPARgamma 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 PPARgamma -specific ligands exclusively recruited DRIP205 but not p160 coactivators to PPARgamma . 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 PPARgamma - and RXR-specific ligands may occur at the level of selective coactivator recruitment.

* Corresponding author. Mailing address: Cell Biology Program---Box 470, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021. Phone: (212) 639-2976. Fax: (212) 717-3298. E-mail: l-freedman{at}ski.mskcc.org.

Molecular and Cellular Biology, November 2000, p. 8008-8017, Vol. 20, No. 21
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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