Activation of specific RXR heterodimers by an antagonist of RXR homodimers

• Published in: Nature (London) Vol. 383; no. 6599; pp. 450 - 453
• Main Authors: Lala, Deepak S, Mukherjee, Ranjan, Schulman, Ira G, Koch, Stacie S. Canan, Dardashti, Laura J, Nadzan, Alex M, Croston, Glenn E, Evans, Ronald M, Heyman, Richard A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 03.10.1996; Nature Publishing Group
• Subjects: Biological and medical sciences; Cellular biology; Dimerization; DNA-Binding Proteins - metabolism; Drosophila Proteins; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation; Genes; Ligands; Molecular and cellular biology; Molecular genetics; Nicotinic Acids - pharmacology; Nuclear Receptor Co-Repressor 2; Pharmacology; Proteins; Receptors, Cytoplasmic and Nuclear - metabolism; Receptors, Retinoic Acid - agonists; Receptors, Retinoic Acid - antagonists & inhibitors; Receptors, Retinoic Acid - chemistry; Receptors, Retinoic Acid - metabolism; Repressor Proteins - metabolism; Retinoid X Receptors; Retinoids - metabolism; Retinoids - pharmacology; TATA-Binding Protein Associated Factors; TATA-Box Binding Protein; Tetrahydronaphthalenes - pharmacology; Trans-Activators - metabolism; Transcription Factor TFIID; Transcription Factors - agonists; Transcription Factors - antagonists & inhibitors; Transcription Factors - chemistry; Transcription Factors - metabolism; Transcription, Genetic - physiology; Transcription. Transcription factor. Splicing. Rna processing; Transfection; Tumor Cells, Cultured; Retinoids; Structure activity relation; Transcription; Biological receptor
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/383450a0

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.