Retinoid X receptor-COUP-TF interactions modulate retinoic acid signaling.
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.
Kliewer
S A
SA
Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA 92037.
Umesono
K
K
Heyman
R A
RA
Mangelsdorf
D J
DJ
Dyck
J A
JA
Evans
R M
RM
D001483:Base Sequence; D051838:COUP Transcription Factor I; D002352:Carrier Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D018168:Receptors, Retinoic Acid; D011987:Receptors, Steroid / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D016415:Sequence Alignment; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation
D051838:COUP Transcription Factor I; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D018168:Receptors, Retinoic Acid; D011987:Receptors, Steroid; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D014157:Transcription Factors