Abstract
We have discovered that the orphan receptor DAX-1 (NROB1) interacts with the estrogen receptors ERalpha and ERbeta. Interaction occurs with ligand-activated ERs in solution and on DNA and is mediated by the unique DAX-1 N-terminal repeat domain. Each of the three repeats contains a leucine-rich receptor-binding motif, known as the LXXLL motif, which is usually found in nuclear receptor coactivators. We have demonstrated that DAX-1 functions as an inhibitor of ER activation in mammalian cells and suggest a mechanism involving two sequential events, occupation of the ligand-induced coactivator-binding surface and subsequent recruitment of corepressors. Accordingly, we propose that DAX-1 itself acts as a corepressor for ERs. Because DAX-1 is coexpressed with ERs in reproductive tissues, these interactions could play significant roles by influencing estrogen signaling pathways. Our results point at functional similarities between DAX-1 and the orphan receptor SHP (NROB2) in that they have acquired features of transcriptional coregulators that are unique for members of the nuclear receptor family.
Highlights
We became interested in coregulators in particular that influence the transcriptional activity of estrogen receptors (ER)
Only Box 3 is conserved between species and has extensive homology to the SHP-Box1 (Fig. 1, A and C), which we have previously demonstrated to be functional as an ER-binding motif [19]
GST1⁄7DAX-1 DBD was found to interact with estradiol-bound ER␣ and ER (Fig. 2A) as well as with various other receptors, indicating that the N-terminal repeat region of DAX-1 may serve as receptor-binding domain
Summary
We became interested in coregulators in particular that influence the transcriptional activity of estrogen receptors (ER). We have provided evidence that SHP, which consists only of an LBD and cannot bind target genes directly, has instead acquired a novel coregulator function by antagonizing the interactions of ERs with associated coactivators [18, 19].
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