Abstract
Many members of the thyroid hormone/retinoid receptor subfamily (type II nuclear receptors) function as heterodimers with the retinoid X receptor (RXR). In heterodimers which are referred to as permissive, such as peroxisome proliferator activated receptor/RXR, both partners can bind cognate ligands and elicit ligand-dependent transactivation. In contrast, the thyroid hormone receptor (TR)/RXR heterodimer is believed to be nonpermissive, where RXR is thought to be incapable of ligand binding and is often referred to as a silent partner. In this report, we used a sensitive derepression assay system that we developed previously to reexamine the TR/RXR interrelationship. We provide functional evidence suggesting that in a TR/RXR heterodimer, the RXR component can bind its ligand in vivo. Ligand binding by RXR does not appear to directly activate the TR/RXR heterodimer; instead, it leads to a (at least transient or dynamic) dissociation of a cellular inhibitor(s)/corepressor(s) from its TR partner and thus may serve to modulate unliganded TR-mediated repression and/or liganded TR-mediated activation. Our results argue against the current silent-partner model for RXR in the TR/RXR heterodimer and reveal an unexpected aspect of cross regulation between TR and RXR.
We thank Richard Heyman for providing retinoids, Ken Takeshita for sharing LGD1069, Ron Evans for the pCMV-RXR plasmids, Inez Rogatsky and Keith Yamamoto for the dominant negative form of GRIP1, Fred Stanley for advice on graphic preparations, Tats Yamada for experimental assistance, and James Yopp for critical reading of the manuscript.
This work was supported by NIH grant DK16636 (to H.H.S.) and NRSA postdoctoral fellowship award DK09581 (to D.L.).