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Molecular Endocrinology 16 (3): 515-528
Copyright © 2002 by The Endocrine Society

Inhibition of Androgen Receptor (AR) Function by the Reproductive Orphan Nuclear Receptor DAX-1

Elin Holter, Noora Kotaja, Sari Mäkela, Leena Strauss, Silke Kietz, Olli A. Jänne, Jan-Åke Gustafsson, Jorma J. Palvimo and Eckardt Treuter

Department of Biosciences at Novum (E.H., S.M., S.K., J.Å.G., E.T.), Department of Medical Nutrition (J.Å.G.), Karolinska Institute, S-14157 Huddinge, Sweden; Department of Anatomy (S.M., L.S.), University of Turku, FIN-20520 Turku, Finland, Department of Clinical Chemistry (O.A.J.); Institute of Biotechnology (J.J.P.); Institute of Biomedicine and Biomedicum Helsinki (N.K., O.A.J., J.J.P.), University of Helsinki, FIN-00014 Helsinki, Finland

Address all correspondence and requests for reprints to: Dr. Eckardt Treuter, Department of Biosciences at Novum, Karolinska Institute, S-14157 Huddinge, Sweden. E-mail: eckardt.treuter{at}cbt.ki.se.

DAX-1 (NROB1) is an atypical member of the nuclear receptor family that is predominantly expressed in mammalian reproductive tissues. While a receptor function of DAX-1 remains enigmatic, previous work has indicated that DAX-1 inhibits the activity of the orphan receptor steroidogenic factor 1 and the estrogen receptors (ERs), presumably via direct occupation of the coactivator-binding surface and subsequent recruitment of additional corepressors. In vivo evidence points at a particular role of DAX-1 for the development and maintenance of male reproductive functions. In this study, we have identified the androgen receptor (AR) NR3C4 as a novel target for DAX-1. We show that DAX-1 potently inhibits ligand-dependent transcriptional activation as well as the interaction between the N- and C-terminal activation domains of AR. We provide evidence for direct interactions of the two receptors that involve the N-terminal repeat domain of DAX-1 and the C-terminal ligand-binding and activation domain of AR. Moreover, DAX-1, known to shuttle between the cytoplasm and the nucleus, is capable of relocalizing AR in both cellular compartments, suggesting that intracellular tethering is associated with DAX-1 inhibition. These results implicate novel inhibitory mechanisms of DAX-1 action with particular relevance for the modulation of androgen-dependent gene transcription in the male reproductive system.




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