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Papers In Press, published online ahead of print October 25, 2000
J. Biol. Chem, 10.1074/jbc.C000567200
Submitted on August 21, 2000
Revised on October 10, 2000
Accepted on October 24, 2000

DAX-1 functions as LXXLL-containing corepressor for activated estrogen receptors

Hui Zhang, Jane S. Thomsen, Lotta Johansson, Jan-Åke Gustafsson, and Eckardt Treuter

Department of Biosciences at Novum, Karolinska Institute, Huddinge/Stockholm S-14157

Corresponding Author: eckardt.treuter{at}cbt.ki.se

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 LXXLL motif, which is usually found in nuclear receptor coactivators. We demonstrate 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. Since 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 both lack the receptor-type DNA-binding domain but instead have acquired features of transcriptional coregulators which are exceptional for members of the nuclear receptor family.


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