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

doi:10.1128/MCB.20.21.8008-8017.2000

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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 $gamma$ (PPAR $gamma$ ) plays a major role in adipogenesis. PPAR $gamma$ binds to DNA as a heterodimerwith retinoid X receptor (RXR), and PPAR $gamma$ -RXR can be activatedby ligands specific for either receptor; the presence of bothligands can result in a cooperative effect on the transactivationof target genes. How these ligands mediate transactivation, however,remains unclear. PPAR $gamma$ is known to interact with both the p160/SRC-1family of coactivators and the distinct, multisubunit coactivatorcomplex called DRIP. A single DRIP subunit, DRIP205 (TRAP220,PBP), binds directly to PPAR $gamma$ . Here we report that PPAR $gamma$ and RXRselectively interacted with DRIP205 and p160 proteins in a ligand-dependentmanner. At physiological concentrations, RXR-specific ligandsonly induced p160 binding to RXR, and PPAR $gamma$ -specific ligands exclusivelyrecruited DRIP205 but not p160 coactivators to PPAR $gamma$ . This selectivitywas not observed in interaction assays off DNA, implying thatthe specificity of coactivator binding in response to ligand isstrongly influenced by the allosteric effects of DNA-bound heterodimers.These coactivator-selective effects were also observed in transient-transfectionassays in the presence of overexpressed p160 or DRIP coactivators.The results suggest that the cooperative effects of PPAR $gamma$ - andRXR-specific ligands may occur at the level of selective coactivatorrecruitment.

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

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