Activation of specific RXR heterodimers by an antagonist of RXR homodimers

Nature. 1996 Oct 3;383(6599):450-3. doi: 10.1038/383450a0.

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.

MeSH terms

  • DNA-Binding Proteins / metabolism
  • Dimerization
  • Drosophila Proteins*
  • Gene Expression Regulation
  • Ligands
  • Nicotinic Acids / pharmacology*
  • Nuclear Receptor Co-Repressor 2
  • 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
  • Transfection
  • Tumor Cells, Cultured

Substances

  • DNA-Binding Proteins
  • Drosophila Proteins
  • LG 100754
  • Ligands
  • Nicotinic Acids
  • Nuclear Receptor Co-Repressor 2
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Retinoic Acid
  • Repressor Proteins
  • Retinoid X Receptors
  • Retinoids
  • TATA-Binding Protein Associated Factors
  • TATA-Box Binding Protein
  • Taf4 protein, Drosophila
  • Tetrahydronaphthalenes
  • Trans-Activators
  • Transcription Factor TFIID
  • Transcription Factors
  • LG 100268