Abstract
Members of the chicken ovalbumin upstream promoter-transcription factor (COUP-TF) subfamily of orphan nuclear receptors, which minimally includes COUP-TFI and ARP1, are highly expressed in brain and are generally considered to be constitutive repressors of transcription. We have used a yeast two-hybrid system to isolate proteins expressed in brain that interact with ARP1. One of the proteins isolated in this screen was Ear2, another orphan receptor that has been suggested to be a member of the COUP-TF subfamily. Here we demonstrate that ARP1 and Ear2 form heterodimers in solution and on directly repeated response elements with high efficiency and a specificity differing from that of homodimeric complexes composed of either receptor. ARP1 and Ear2 were observed to interact in mammalian cells, and the tissue distribution of Ear2 transcripts was found to overlap precisely with the expression pattern of ARP1 in several mouse tissues and embryonal carcinoma cell lines. Heterodimeric interactions between ARP1 and Ear2 may define a distinct pathway of orphan receptor signaling.
Highlights
COUP-TF1 orphan nuclear receptors have been reported to interfere with the signaling pathways of several nuclear receptors including retinoic acid [1,2,3,4,5], thyroid hormone [3], estrogen (6 –9), and vitamin D3 [4] receptors, as well as peroxisome proliferator-activated receptor ␣ [10, 11]
Ligand-dependent interactions were examined in the presence of 1 M 9-cis-retinoic acid (9cRA)
In addition to the ARP11⁄7Ear2 complex described in this report, we have observed the formation of COUP-TFI1⁄7ARP1 as well as COUP-TFI1⁄7Ear2 complexes on a DR1-type response element
Summary
COUP-TF1 orphan nuclear receptors have been reported to interfere with the signaling pathways of several nuclear receptors including retinoic acid [1,2,3,4,5], thyroid hormone [3], estrogen (6 –9), and vitamin D3 [4] receptors, as well as peroxisome proliferator-activated receptor ␣ [10, 11]. Modulation of multiple signaling pathways by COUP-TF subfamily members: 1) competition for DNA response element binding, 2) inactive heterocomplex formation including titration of retinoid X receptor (RXR), 3) active silencing of basal transcription, and 4) transcriptional transrepression [16] Of these potential mechanisms, competition for binding to response elements is well documented and is based upon the ability of COUP-TF proteins to bind a large variety of response elements [16]. Other groups consider Ear to be a member of COUP-TF subfamily based on the capacity of this protein to form homodimeric, DNA binding complexes and to repress ligand-dependent activation of target genes mediated by other nuclear receptors, such as retinoic acid [1, 20] and estrogen [7,8,9] receptors, in a manner similar to that of COUPTFI and ARP1. Knock-out of the ARP1 gene in the mouse is apparently embryonic lethal [16]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
