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J. Biol. Chem., Vol. 279, Issue 9, 7427-7437, February 27, 2004

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Novel Roles of Retinoid X Receptor (RXR) and RXR Ligand in Dynamically Modulating the Activity of the Thyroid Hormone Receptor/RXR Heterodimer^*

Dangsheng Li, Tatsuya Yamada, Fang Wang, A. Igor Vulin, and Herbert H. Samuels

From the Department of Pharmacology, New York University School of Medicine, New York, New York 10016

Many members of the type II nuclear receptor subfamily function as heterodimers with the retinoid X receptor (RXR). A permissive heterodimer (e.g. peroxisome proliferator-activated receptor/RXR) allows for ligand binding by both partners of the receptor complex. In contrast, RXR has been thought to be incapable of ligand binding in a nonpermissive heterodimer, such as that of thyroid hormone receptor (TR)/RXR, where it has been referred to as a silent partner. However, we recently presented functional evidence suggesting that RXR in the TR/RXR heterodimer can bind its natural ligand 9-cis-RA in cells. Here we extended our study of the interrelationship of TR and RXR. We examined the potential modulatory effect of RXR and its ligand on the activity of TR, primarily using a Gal4-TR chimera. This study led to several novel and unexpected findings: 1) heterodimerization of apo-RXR (in the absence of 9-cis-RA) with Gal4-TR inhibits T3-mediated transactivation; 2) the inhibition of Gal4-TR activity by RXR is further enhanced by 9-cis-RA; 3) two different RXR subtypes ( and ) differentially modulate the activity of Gal4-TR; 4) the N-terminal A/B domains of RXR and are largely responsible for their differential modulation of TR activity; and 5) the RXR ligand 9-cis-RA appears to differentially affect T3-mediated transactivation from the Gal4-TR/RXR (which is inhibited by 9-cis-RA) and TRE-bound TR/RXR (which is further activated by 9-cis-RA) heterodimers. Taken together, these results further support our recent proposal that the RXR component in a TR/RXR heterodimer is not silent and, more importantly, reveal novel aspects of regulation of the activity of the TR/RXR heterodimer by RXR and RXR ligand.

Received for publication, October 22, 2003

^* This work was supported by National Institutes of Health Grant DK16636 (to H. H. S.) and National Research Service Award DK09581 (to D. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence may be addressed: Dept. of Pharmacology, MSB 424, NYU School of Medicine, 550 First Ave., New York, NY 10016. Tel.: 212-263-6279; Fax: 212-263-7133; E-mail: lid01{at}med.nyu.edu. To whom correspondence may be addressed: Dept. of Pharmacology, MSB 424, NYU School of Medicine, 550 First Ave., New York, NY 10016. Tel.: 212-263-6279; Fax: 212-263-7133; E-mail: herbert.samuels{at}med.nyu.edu.

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