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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
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
(PPAR
) plays a
major role in adipogenesis. PPAR
binds to DNA as a heterodimer with retinoid X receptor (RXR), and PPAR
-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. PPAR
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
. Here we report that PPAR
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
-specific ligands exclusively recruited DRIP205 but not p160
coactivators to PPAR
. 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
- 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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