title: Activation of specific RXR heterodimers by an antagonist of RXR homodimers.
abstract: Retinoid X receptor (RXR) plays a central role in the regulation of many intracellular receptor signalling pathways and can mediate ligand-dependent transcription, acting as a homodimer or as a heterodimer. Here we identify an antagonist towards RXR homodimers which also functions as an agonist when RXR is paired as a heterodimer to specific partners, including peroxisome proliferator-activated receptor and retinoic acid receptor. This dimer-selective ligand confers differential interactions on the transcription machinery: the antagonist promotes association with TAF110 (TATA-binding protein (TBP)-associated factor 110) and the co-repressor SMRT, but not with TBP, and these properties are distinct from pure RXR agonists. This unique class of RXR ligands will provide a means to control distinct target genes at the level of transcription and allow the development of retinoids with a new pharmacological action.
authors.affiliation: Department of Retinoid Research, New Leads Ligand Pharmaceuticals, San Diego, California 92121, USA.
authors.forename: D S
authors.initials: DS
authors.lastname: Lala
authors.forename: R
authors.initials: R
authors.lastname: Mukherjee
authors.forename: I G
authors.initials: IG
authors.lastname: Schulman
authors.forename: S S
authors.initials: SS
authors.lastname: Koch
authors.forename: L J
authors.initials: LJ
authors.lastname: Dardashti
authors.forename: A M
authors.initials: AM
authors.lastname: Nadzan
authors.forename: G E
authors.initials: GE
authors.lastname: Croston
authors.forename: R M
authors.initials: RM
authors.lastname: Evans
authors.forename: R A
authors.initials: RA
authors.lastname: Heyman
mesh_terms: D004268:DNA-Binding Proteins / Q000378:metabolism; D019281:Dimerization; D029721:Drosophila Proteins; D005786:Gene Expression Regulation; D008024:Ligands; D009539:Nicotinic Acids / Q000494:pharmacology*; D056985:Nuclear Receptor Co-Repressor 2; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D047488:Retinoid X Receptors; D012176:Retinoids / Q000378:metabolism / Q000494:pharmacology*; D035381:TATA-Binding Protein Associated Factors; D035181:TATA-Box Binding Protein; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D015534:Trans-Activators / Q000378:metabolism; D035362:Transcription Factor TFIID; D014157:Transcription Factors / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; C101596:LG 100754; D008024:Ligands; D009539:Nicotinic Acids; D056985:Nuclear Receptor Co-Repressor 2; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D047488:Retinoid X Receptors; D012176:Retinoids; D035381:TATA-Binding Protein Associated Factors; D035181:TATA-Box Binding Protein; C103338:Taf4 protein, Drosophila; D013764:Tetrahydronaphthalenes; D015534:Trans-Activators; D035362:Transcription Factor TFIID; D014157:Transcription Factors; C095104:LG 100268