Inhibition of androgen receptor (AR) function by the reproductive orphan nuclear receptor DAX-1.
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.
Mesh Terms:
Animals, COS Cells, Cell Nucleus, Cytoplasm, DAX-1 Orphan Nuclear Receptor, DNA-Binding Proteins, Fluorescent Antibody Technique, Indirect, Gene Expression, Glutathione Transferase, Green Fluorescent Proteins, Hela Cells, Humans, Immunohistochemistry, Immunosorbent Techniques, Luciferases, Luminescent Proteins, Male, Microscopy, Confocal, Mutation, Promoter Regions, Genetic, Receptors, Androgen, Receptors, Retinoic Acid, Recombinant Fusion Proteins, Repressor Proteins, Response Elements, Steroidogenic Factor 1, TATA Box, Transcription Factors, Transcription, Genetic, Transfection
Animals, COS Cells, Cell Nucleus, Cytoplasm, DAX-1 Orphan Nuclear Receptor, DNA-Binding Proteins, Fluorescent Antibody Technique, Indirect, Gene Expression, Glutathione Transferase, Green Fluorescent Proteins, Hela Cells, Humans, Immunohistochemistry, Immunosorbent Techniques, Luciferases, Luminescent Proteins, Male, Microscopy, Confocal, Mutation, Promoter Regions, Genetic, Receptors, Androgen, Receptors, Retinoic Acid, Recombinant Fusion Proteins, Repressor Proteins, Response Elements, Steroidogenic Factor 1, TATA Box, Transcription Factors, Transcription, Genetic, Transfection
Mol. Endocrinol.
Date: Mar. 01, 2002
PubMed ID: 11875111
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