title: Novel roles of retinoid X receptor (RXR) and RXR ligand in dynamically modulating the activity of the thyroid hormone receptor/RXR heterodimer.
abstract: 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-RXRalpha (in the absence of 9-cis-RA) with Gal4-TR inhibits T3-mediated transactivation; 2) the inhibition of Gal4-TR activity by RXRalpha is further enhanced by 9-cis-RA; 3) two different RXR subtypes (alpha and beta) differentially modulate the activity of Gal4-TR; 4) the N-terminal A/B domains of RXR alpha and beta 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/RXRalpha (which is inhibited by 9-cis-RA) and TRE-bound TR/RXRalpha (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.
authors.affiliation: Department of Pharmacology, New York University School of Medicine, New York, New York 10016, USA. lid01@med.nyu.edu
authors.forename: Dangsheng
authors.initials: D
authors.lastname: Li
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Yamada
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.forename: A Igor
authors.initials: AI
authors.lastname: Vulin
authors.forename: Herbert H
authors.initials: HH
authors.lastname: Samuels
mesh_terms: D000077556:Alitretinoin; D004268:DNA-Binding Proteins; D019281:Dimerization; D015870:Gene Expression; D006367:HeLa Cells; D006801:Humans; D018168:Receptors, Retinoic Acid / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D011988:Receptors, Thyroid Hormone / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D047488:Retinoid X Receptors; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics; D014157:Transcription Factors / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D014212:Tretinoin / Q000378:metabolism* / Q000494:pharmacology; D014284:Triiodothyronine / Q000494:pharmacology
chemical_list: D004268:DNA-Binding Proteins; C052130:GAL4 protein, S cerevisiae; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D011993:Recombinant Fusion Proteins; D047488:Retinoid X Receptors; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D014284:Triiodothyronine; D000077556:Alitretinoin; D014212:Tretinoin