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Activation of specific RXR heterodimers by an antagonist of RXR homodimers

Nature volume 383, pages 450–453 (1996)Cite this article

Abstract

RETINOID X receptor (RXR) plays a central role in the regulation of many intracellular receptor signalling pathways1 and can mediate ligand-dependent transcription, acting as a homodimer or as a heterodimer1–6. 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 peroxi-some 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 SMRT7, 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.

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Author notes

  1. Ira G. Schulman

    Present address: Department of Retinoid Research, Ligand Pharmaceuticals, 10255 Science Center Drive, San Diego, California, 92121, USA

Authors and Affiliations

  1. Department of Retinoid Research, Ligand Pharmaceuticals, 10255 Science Center Drive, San Diego, California, 92121, USA

    Deepak S. Lala & Richard A. Heyman

  2. Department of Cardiovascular Research, Ligand Pharmaceuticals, 10255 Science Center Drive, San Diego, California, 92121, USA

    Ranjan Mukherjee

  3. Department of Retinoid Chemistry, Ligand Pharmaceuticals, 10255 Science Center Drive, San Diego, California, 92121, USA

    Stacie S. Canan Koch, Laura J. Dardashti & Alex M. Nadzan

  4. Department of New Leads, Ligand Pharmaceuticals, 10255 Science Center Drive, San Diego, California, 92121, USA

    Glenn E. Croston

  5. The Salk Institute for Biological Studies, La Jolla, California, 92037, USA

    Ira G. Schulman & Ronald M. Evans

Authors
  1. Deepak S. Lala
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Lala, D., Mukherjee, R., Schulman, I. et al. Activation of specific RXR heterodimers by an antagonist of RXR homodimers. Nature 383, 450–453 (1996). https://doi.org/10.1038/383450a0

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