Retinoid X receptor-COUP-TF interactions modulate retinoic acid signaling

Steven A. Kliewer, Kazuhiko Umesono, Richard A. Heyman, David J. Mangelsdorf, Jacqueline A. Dyck, Ronald M. Evans

Research output: Contribution to journalArticlepeer-review

100 Scopus citations


We have recently described the properties of direct repeats (DRs) of the half-site AGGTCA as hormone response elements (HREs). According to our results, spacing the half sites by 3, 4, or 5 nucleotides determines specificity of response for vitamin D3, thyroid hormone, and retinoic acid receptors, respectively. This so-called 3-4-5 rule led to the prediction that remaining spacing options of 0, 1, and 2 might serve as targets for other nuclear receptors. A concurrent prediction is that receptors recognizing common sites might display more complex or combinatorial interactions. In exploring these predictions, we discovered that both the retinoid X receptor (RXR) and COUP-TF bind preferentially to a DR-1 motif. In vivo, RXR and COUP- TF display antagonistic action such that RXR-mediated activation is fully repressed by COUP-TF. In vitro studies reveal that COUP-TF and RXR form heterodimers on DR-1. Thus, these results support a general proposal in which the half-site spacing preferences may be used as a means to decipher potentially complex and interactive regulatory circuits.

Original languageEnglish (US)
Pages (from-to)1448-1452
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number4
StatePublished - 1992


  • heterodimer
  • hormone response element
  • orphan receptor

ASJC Scopus subject areas

  • General


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