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

Holter, Elin; Kotaja, Noora; Mäkelä, Sari; Strauss, Leena; Kietz, Silke; Jänne, Olli A.; Gustafsson, Jan‐Åke; Palvimo, Jorma J.; Treuter, Eckardt

doi:10.1210/mend.16.3.0804

Cited by 106 publications

(50 citation statements)

References 57 publications

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“…Although in vitro interactions between DAX-1 and AR have been reported (15), there have been no reports of interactions of endogenous DAX-1 and AR. Neither functional nor physical interactions between PR and DAX-1 have been reported.…”

Section: Discussionmentioning

confidence: 99%

“…Since the N terminus has 3 LXXLL-like motifs, it is possible that this is the interacting portion of DAX-1, although the C terminus is required for repression. Holter et al (15) found that the N terminus of DAX-1 was sufficient to cause aberrant localization of AR in the cytoplasm implicating this region in a physical interaction. In contrast, the N terminus of DAX-1 is sufficient to partially repress the activity of PR albeit to a lesser extent than the full-length (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Holter et al (15) has shown in vitro interaction between AR and DAX-1, Dotzlaw et al (35) has shown in vitro interaction between AR and SMRT and Liao et al (36) has shown an in vivo interaction between AR and SMRT. In contrast, only the in vitro interaction between PR and SMRT has been shown (33).…”

Section: Dax-1 Smrt and Ncor Repress Both Agonist-and Partialmentioning

confidence: 99%

“…Neither DAX-1 nor SMRT Reduce the Ability of AR and PR to Bind DNA in a Promoter Interference Assay-Holter et al (15) have suggested that DAX-1 may prevent AR from localizing to the nucleus and thus binding to DNA. To test whether DAX-1 or SMRT reduce DNA binding of AR or PR, we performed simultaneous promoter interference assays using a CAT reporter and a transrepression assay using a luciferase reporter.…”

Section: Dax-1 Represses the Activity Of The Ar⌬lbd Mutant But Not Ofmentioning

confidence: 99%

“…In contrast, SMRT represses both AR and PR in the presence of either agonist or antagonist. During the preparation of this article, Holter et al (15) reported that DAX-1 represses AR activity and suggested that DAX-1 can cause mislocalization of AR to the cytoplasm in the presence of agonist. However, our studies using a promoter interference assay, suggest that DAX-1 does not disrupt the interaction of either AR or PR with DNA.…”

mentioning

confidence: 97%

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Repressors of Androgen and Progesterone Receptor Action

Agoulnik

Krause

Bingman

et al. 2003

Journal of Biological Chemistry

124

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Androgen and progesterone receptors (AR and PR) are two determining factors in gonadal differentiation that are highly expressed in developing and mature gonads. Loss of AR results in XY sex reversal and mutations causing reduced AR activity lead to varying degrees of defects in masculinization. Female PR knockout mice are infertile due to ovarian defects. While much has been discovered about positive regulation of these receptors by coactivators little is known about repression of the transcriptional activity of AR and PR in the presence of agonists. In this study we assessed the effect of SMRT and DAX-1 on AR and PR activity in the presence of both agonists and partial antagonists. We show that SMRT and DAX-1 repress agonist-dependent activity of both receptors, and the mechanism of repression includes disruption of the receptor dimer interactions rather than recruitment of histone deacetylases. We demonstrate that endogenous agonist-bound PR and DAX-1 in T47D breast cancer cells and endogenous AR and DAX-1 in LNCaP prostate cancer cells can be coimmunoprecipitated suggesting that the interaction is physiological. Surprisingly, although DAX-1 represses partial antagonist activity of AR, it was ineffective in repressing partial antagonist induced activity of PR. In contrast to most reported repressors, the expression of DAX-1 is restricted. We found that although DAX-1 is expressed in normal human prostate, its expression is strongly reduced in benign prostatic hyperplasia suggesting that DAX-1 plays a role in limiting AR activity in prostate.Nuclear receptors are regulated both by coactivators and by corepressors. Although steroid receptor coactivators have been studied extensively, less is known about corepressors of agonist activated steroid receptors. Androgens, acting through AR, 1 play a role in both benign prostatic hyperplasia (BPH) and prostate cancer. In both cases, reduction in AR activity is an important component of treatment, although fully effective treatments are not yet available. Two well characterized corepressors of thyroid receptor (TR) activity, NCoR (nuclear receptor co-repressor) and SMRT (silencing mediator for retinoid acid receptor (RAR) and TR), have been identified previously (1, 2). They appear to work through binding to TR aporeceptor, recruiting complexes containing histone deacetylases (HDACs); they dissociate from the receptor upon agonist binding allowing coactivator complexes to form (3). In the case of estrogen receptor (ER), these repressors interact with the antagonist bound receptor through a region that largely overlaps with the coactivator binding interface, and recruit HDACs (4). An orphan nuclear receptor DAX-1 (dosage sex reversal, adrenal hypoplasia congenita critical region on the X chromosome, gene 1) has been reported to inhibit steroidogenic factor 1 (SF-1) and ER activity (5, 6). DAX-1 is an atypical nuclear receptor containing an ssDNA/RNA binding domain in its N terminus and a multihelical C-terminal domain, a putative ligand binding domain (LBD) (7). DAX-1 i...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Dax-1 Smrt and Ncor Repress Both Agonist-and Partialmentioning

confidence: 99%

Section: Dax-1 Represses the Activity Of The Ar⌬lbd Mutant But Not Ofmentioning

confidence: 99%

mentioning

confidence: 97%

See 3 more Smart Citations

Repressors of Androgen and Progesterone Receptor Action

Agoulnik

Krause

Bingman

et al. 2003

Journal of Biological Chemistry

124

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Age‐dependent differential expression of genes involved in steroid signalling pathway in the brain of protandrous black porgy, Acanthopagrus schlegeli

Tomy

Huang

et al. 2009

Developmental Neurobiology

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ABSTRACT:The mechanisms underlying brain sex differentiation in animals are poorly understood. In the present study, using black porgy, Acanthopagrus schlegeli, as primary experimental model, we investigated the temporal expression patterns of receptors for androgen (ar) and estrogen (esr1 and esr2a) in the brain during posthatching ages and analyzed them against the timing of gonadal germ cell development. We hypothesized that endogenous estrogens naturally masculinize the brain of black porgy. The expression of sex steroid receptors was studied in relation to a wider suite of other related genes (nr5a2, nr0b1, star, and cyp19a1b) to provide some insight into the monomale sex differentiation pattern observed in this species. Our results revealed a highly significant increase in esr1 together with the increase in esr2a at 120 dph (days posthatching), suggesting a significant role for esr in sex differentiation in this species. Temporal expression patterns of nr5a2, nr0b1, star, sex steroid receptors, and cyp19a1b in the brain provided evidence for their physiological roles in the monomale sex differentiation in this species. The expression of nr5a2, star, ar, esr1, esr2a, and cyp19a1b increased at 120 dph, a period when brain sex differentiation probably occurs in this species. The study also suggests that neurosteroidogenesis in black porgy may be regulated by both nr5a2-dependent and nr5a2-independent mechanisms. The results demonstrated striking differences in the abundance of the gene transcripts in discrete brain region throughout ontogeny. In addition, the sex steroid hormone levels and aromatase activity in brain at different developmental states and the changes in the gene expression patterns in response to aromatase inhibitor treatment are also discussed. ' 2009 Wiley Periodicals, Inc. Develop Neurobiol

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Role of SF‐1 and DAX‐1 during differentiation of P19 cells by retinoic acid

Teets

Soprano

2012

Journal Cellular Physiology

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Retinoic acid (RA) is critical for embryonic development and cellular differentiation. Previous work in our laboratory has shown that blocking the RA-dependent increase in pre-β cell leukemia transcription factors (PBX) mRNA and protein levels in P19 cells prevents endodermal and neuronal differentiation. Dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 (DAX-1) and steroidogenic factor (SF-1) were found by microarray analysis to be regulated by PBX in P19 cells. To determine the roles of DAX-1 and SF-1 during RA-dependent differentiation, P19 cells that inducibly express either FLAG-DAX-1 or FLAG-SF-1 were prepared. Unexpectedly, overexpression of DAX-1 had no effect on the RA-induced differentiation of P19 cells to either endodermal or neuronal cells. However, SF-1 overexpression prevented the RA-dependent loss of OCT-4, DAX-1 and the increase in COUP-TFI, COUP-TFII and ETS-1 mRNA levels during the commitment stages of both endodermal and neuronal differentiation. Surprisingly, continued expression of SF-1 for seven days caused the RA-independent loss of OCT-4 protein and RA-dependent loss of SSEA-1 expression. Despite the loss of well characterized pluripotency markers, these cells did not terminally differentiate into either endodermal or neuronal cells. Instead, the cells gained the expression of many steroidogenic enzymes with a pattern consistent with adrenal cells. Finally, we found evidence for a feedback loop in which PBX reduces SF-1 mRNA levels while continued SF-1 expression blocks the RA-dependent increase in PBX levels. Taken together, these data demonstrate that SF-1 plays a dynamic role during the differentiation of P19 cells and potentially during early embryogenesis.

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

Cited by 106 publications

References 57 publications

Repressors of Androgen and Progesterone Receptor Action

Repressors of Androgen and Progesterone Receptor Action

Age‐dependent differential expression of genes involved in steroid signalling pathway in the brain of protandrous black porgy, Acanthopagrus schlegeli

Role of SF‐1 and DAX‐1 during differentiation of P19 cells by retinoic acid

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