Inhibition of androgen receptor (AR) function by the reproductive orphan nuclear receptor DAX-1

Mol Endocrinol. 2002 Mar;16(3):515-28. doi: 10.1210/mend.16.3.0804.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgen Receptor Antagonists*
  • Animals
  • COS Cells
  • Cell Nucleus / metabolism
  • Cytoplasm / metabolism
  • DAX-1 Orphan Nuclear Receptor
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / pharmacology
  • DNA-Binding Proteins / physiology*
  • Fluorescent Antibody Technique, Indirect
  • Gene Expression
  • Glutathione Transferase / genetics
  • Green Fluorescent Proteins
  • HeLa Cells
  • Humans
  • Immunohistochemistry
  • Immunosorbent Techniques
  • Luciferases / genetics
  • Luminescent Proteins / genetics
  • Male
  • Microscopy, Confocal
  • Mutation
  • Promoter Regions, Genetic
  • Receptors, Androgen / genetics
  • Receptors, Androgen / physiology*
  • Receptors, Retinoic Acid / genetics
  • Receptors, Retinoic Acid / physiology*
  • Recombinant Fusion Proteins
  • Repressor Proteins / pharmacology
  • Response Elements
  • Steroidogenic Factor 1
  • TATA Box
  • Transcription Factors / genetics
  • Transcription Factors / pharmacology
  • Transcription Factors / physiology*
  • Transcription, Genetic / drug effects
  • Transfection


  • Androgen Receptor Antagonists
  • DAX-1 Orphan Nuclear Receptor
  • DNA-Binding Proteins
  • Luminescent Proteins
  • NR0B1 protein, human
  • NR5A1 protein, human
  • Receptors, Androgen
  • Receptors, Retinoic Acid
  • Recombinant Fusion Proteins
  • Repressor Proteins
  • Steroidogenic Factor 1
  • Transcription Factors
  • Green Fluorescent Proteins
  • Luciferases
  • Glutathione Transferase