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.
Holter
Elin
E
Department of Biosciences at Novum, Karolinska Institute, S-14157 Huddinge, Sweden.
Kotaja
Noora
N
Mäkela
Sari
S
Strauss
Leena
L
Kietz
Silke
S
Jänne
Olli A
OA
Gustafsson
Jan-Ake
JA
Palvimo
Jorma J
JJ
Treuter
Eckardt
E
D059002:Androgen Receptor Antagonists; D000818:Animals; D019556:COS Cells; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D019084:Fluorescent Antibody Technique, Indirect; D015870:Gene Expression; D005982:Glutathione Transferase / Q000235:genetics; D049452:Green Fluorescent Proteins; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D007163:Immunosorbent Techniques; D008156:Luciferases / Q000235:genetics; D008164:Luminescent Proteins / Q000235:genetics; D008297:Male; D018613:Microscopy, Confocal; D009154:Mutation; D011401:Promoter Regions, Genetic; D011944:Receptors, Androgen / Q000235:genetics / Q000502:physiology*; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins / Q000494:pharmacology; D020218:Response Elements; D054339:Steroidogenic Factor 1; D016385:TATA Box; D014157:Transcription Factors / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
D059002:Androgen Receptor Antagonists; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins; D008164:Luminescent Proteins; C539965:NR0B1 protein, human; C515057:NR5A1 protein, human; D011944:Receptors, Androgen; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D054339:Steroidogenic Factor 1; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; D008156:Luciferases; D005982:Glutathione Transferase