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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
(PPAR
) Heterodimers:
Intermolecular Synergy Requires Only the PPAR
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
(PPAR
), 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
and RXR has a synergistic effect on the transactivation of reporter genes and on adipocyte differentiation in cultured cells. Mutation of
the PPAR
hormone-dependent activation domain (named
c or AF-2)
inhibits the ability of RXR-PPAR
heterodimers to respond to ligands
specific for either subunit. In contrast, the ability of RXR- and
PPAR
-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
, 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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