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, Eckardt Treuter

Research output: Contribution to journalArticle

107 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)515-528
Number of pages14
JournalMolecular Endocrinology
Volume16
Issue number3
DOIs
StatePublished - 2002

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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