Ligand-independent actions of the orphan receptors/corepressors DAX-1 and SHP in metabolism, reproduction and disease

Ehrlund, Anna; Treuter, Eckardt

doi:10.1016/j.jsbmb.2011.04.007

Cited by 31 publications

(31 citation statements)

References 135 publications

(126 reference statements)

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“…2). Although it is expressed primarily in several hormone-producing tissues, including adrenal glands, pituitary gland, and hypothalamus, there is increasing evidence showing the presence of DAX-1 in human and animal livers (Ehrlund and Treuter, 2012). Our study found that there is remarkable expression of DAX-1 and its mRNA in both HepG2 cells and primary human hepatocytes (Figs.…”

Section: Discussionsupporting

confidence: 49%

“…1, 2, and 5). In general, DAX-1 serves as negative regulator of transcriptional activity of many nuclear receptors, such as HNF4a, LXRa, FXR, nerve growth factor-inducible gene B (Nur77), estrogen receptor, thyroid receptor, steroidogenic factor 1, androgen receptor, glucocorticoid receptor, liver receptor homolog-1, and peroxisome proliferatoractivated receptor-g (Nedumaran et al, 2009;Ehrlund and Treuter, 2012;Laurenzana et al, 2012). Mutations of DAX-1 result in both Xlinked congenital adrenal hypoplasia and hypogonadotropic hypogonadism.…”

Section: Discussionmentioning

confidence: 99%

“…DAX-1 appears to have a further role in hepatic lipogenesis and gluconeogenesis. DAX-1 can compete with NR coactivators such as PGC1a, glutamate receptor-interacting protein 1, and steroid receptor coactivator-1, and it recruits corepressors such as nuclear receptor corepressor 1 and Alien (Ehrlund and Treuter, 2012). The revealed crystal structure of DAX-1 bound to liver receptor homolog 1 has shown that DAX-1 could function as a ligandindependent NR as well as a competitive transcriptional corepressor (Fannin et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

MicroRNA-561 Promotes Acetaminophen-Induced Hepatotoxicity in HepG2 Cells and Primary Human Hepatocytes through Downregulation of the Nuclear Receptor Corepressor Dosage-Sensitive Sex-Reversal Adrenal Hypoplasia Congenital Critical Region on the X Chromosome, Gene 1 (DAX-1)

Yang

et al. 2013

Drug Metab Dispos

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One of the major mechanisms involved in acetaminophen (APAP)-induced hepatotoxicity is hepatocyte nuclear factor 4a (HNF4a)-mediated activation of pregnane X receptor (PXR) and constitutive androstane receptor (CAR). In the present study, we investigated the role of miR-561 and its target gene DAX-1 encoding a corepressor of HNF4a in the process of APAP-induced hepatotoxicity. We used both human hepatocellular liver carcinoma cell line (HepG2) cells and primary human hepatocytes in this study and monitored the levels of reactive oxygen species, lactate dehydrogenase, and glutathione. Our bioinformatics study suggests an association between miR-561 and DAX-1, but not HNF4a. Treatment of HepG2 cells with APAP significantly reduced the expression of DAX-1 in a concentration-dependent manner. miR-561 was induced by APAP treatment in HepG2 cells. Transfection of HepG2 cells with an miR-561 mimic exacerbated APAP-induced hepatotoxicity. HNF4a is physically associated with DAX-1 in HepG2 cells. A decreased protein level of DAX-1 by APAP treatment was also enhanced by miR-561 mimic transfection in HepG2 cells and primary human hepatocytes. The basal and APAP-induced expression of PXR and CAR was enhanced by miR-561 mimic transfection; however, transfection of HepG2 cells or primary human hepatocytes with a miR-561 inhibitor or DAX-1 small interfering RNA reversed these effects. Additionally, the chromatin immunoprecipitation assay revealed that recruitment of DAX-1 onto the PXR promoter was inversely correlated with the recruitment of peroxisome proliferator-activated receptor-a coactivator-1a and HNF4a on APAP treatment. These results indicate that miR-561 worsens APAP-induced hepatotoxicity via inhibition of DAX-1 and consequent transactivation of nuclear receptors.

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Section: Discussionsupporting

confidence: 49%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

MicroRNA-561 Promotes Acetaminophen-Induced Hepatotoxicity in HepG2 Cells and Primary Human Hepatocytes through Downregulation of the Nuclear Receptor Corepressor Dosage-Sensitive Sex-Reversal Adrenal Hypoplasia Congenital Critical Region on the X Chromosome, Gene 1 (DAX-1)

Yang

et al. 2013

Drug Metab Dispos

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“…On the basis of the results of the McDonnell panel peptide screening and the fact that DAX-1 and SHP are related (Ehrlund and Treuter, 2012), we tested DAX-1 and SHP for interaction with CAR1 in reporter assays in COS-1 cells. Both DAX-1 and SHP markedly repressed the ability of CAR1 to activate the 2B6XREM luciferase reporter in a dose-dependent manner; however, DAX-1 exhibited much more potent inhibition (ϳ10ϫ) than SHP (Fig.…”

Section: Resultsmentioning

confidence: 99%

The Orphan Nuclear Receptor DAX-1 Functions as a Potent Corepressor of the Constitutive Androstane Receptor (NR1I3)

et al. 2012

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Regulation of gene transcription is controlled in part by nuclear receptors that function coordinately with coregulator proteins. The human constitutive androstane receptor (CAR; NR1I3) is expressed primarily in liver and regulates the expression of genes involved in xenobiotic metabolism as well as hormone, energy, and lipid homeostasis. In this report, DAX-1, a nuclear receptor family member with corepressor properties, was identified as a potent CAR regulator. Results of transaction and mutational studies demonstrated that both DAX-1's downstream LXXLL and its PCFQVLP motifs were critical contributors to DAX-1's corepression activities, although two other LXXM/LL motifs located nearer the N terminus had no impact on the CAR functional interaction. Deletion of DAX-1's C-terminal transcription silencing domain restored CAR1 transactivation activity in reporter assays to approximately 90% of control, demonstrating its critical function in mediating the CAR repression activities. Furthermore, results obtained from mammalian two-hybrid experiments assessing various domain configurations of the respective receptors showed that full-length DAX-1 inhibited the CAR-SRC1 interaction by approximately 50%, whereas the same interaction was restored to 90% of control when the DAX-1 transcription silencing domain was deleted. Direct interaction between CAR and DAX-1 was demonstrated with both alpha-screen and coimmunoprecipitation experiments, and this interaction was enhanced in the presence of the CAR activator 6-(4-chlorophenyl)imidazo[2,1-b]thiazole-5-carbaldehyde O- (3,4-dichlorobenzyl)oxime (CITCO). Results obtained in primary human hepatocytes further demonstrated DAX-1 inhibition of CAR-mediated CITCO induction of the CYP2B6 target gene. The results of this investigation identify DAX-1 as a novel and potent CAR corepressor and suggest that DAX-1 functions as a coordinate hepatic regulator of CAR's biological function.

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“…DAX-1 and SHP homologues are present throughout vertebrates, indicating a paralogous origin through duplication from a common ancestral gene. Intriguingly, DAX-1 and SHP both have important but distinct functions in metabolic and reproductive processes and share common mechanisms of gene regulation (reviewed in [14]). …”

Section: Cloning and Structure Of Dax-1: An Unusual Orphan Receptormentioning

confidence: 99%

Role of Orphan Nuclear Receptor DAX-1/NR0B1 in Development, Physiology, and Disease

Lalli

2014

Advances in Biology

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is an unusual orphan receptor that has a pivotal role in the development and function of steroidogenic tissues and of the reproductive axis. Recent studies have also indicated that this transcription factor has an important function in stem cell biology and in several types of cancer. Here I critically review the most important findings on the role of DAX-1 in development, physiology, and disease of endocrine tissues since the cloning of its gene twenty years ago.

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Ligand-independent actions of the orphan receptors/corepressors DAX-1 and SHP in metabolism, reproduction and disease

Cited by 31 publications

References 135 publications

MicroRNA-561 Promotes Acetaminophen-Induced Hepatotoxicity in HepG2 Cells and Primary Human Hepatocytes through Downregulation of the Nuclear Receptor Corepressor Dosage-Sensitive Sex-Reversal Adrenal Hypoplasia Congenital Critical Region on the X Chromosome, Gene 1 (DAX-1)

MicroRNA-561 Promotes Acetaminophen-Induced Hepatotoxicity in HepG2 Cells and Primary Human Hepatocytes through Downregulation of the Nuclear Receptor Corepressor Dosage-Sensitive Sex-Reversal Adrenal Hypoplasia Congenital Critical Region on the X Chromosome, Gene 1 (DAX-1)

The Orphan Nuclear Receptor DAX-1 Functions as a Potent Corepressor of the Constitutive Androstane Receptor (NR1I3)

Role of Orphan Nuclear Receptor DAX-1/NR0B1 in Development, Physiology, and Disease

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