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Molecular Pharmacology

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Research ArticleArticle

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

Elizabeth M. Laurenzana, Tao Chen, Malavika Kannuswamy, Brian E. Sell, Stephen C. Strom, Yong Li and Curtis J. Omiecinski
Molecular Pharmacology November 2012, 82 (5) 918-928; DOI: https://doi.org/10.1124/mol.112.080721
Elizabeth M. Laurenzana
Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, Pennsylvania (E.M.L., T.C., M.K., B.E.S., C.J.O.); and Departments of Pathology (S.C.S.) and Pharmaceutical Sciences (Y.L.), University of Pittsburgh, Pittsburgh, Pennsylvania
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Tao Chen
Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, Pennsylvania (E.M.L., T.C., M.K., B.E.S., C.J.O.); and Departments of Pathology (S.C.S.) and Pharmaceutical Sciences (Y.L.), University of Pittsburgh, Pittsburgh, Pennsylvania
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Malavika Kannuswamy
Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, Pennsylvania (E.M.L., T.C., M.K., B.E.S., C.J.O.); and Departments of Pathology (S.C.S.) and Pharmaceutical Sciences (Y.L.), University of Pittsburgh, Pittsburgh, Pennsylvania
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Brian E. Sell
Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, Pennsylvania (E.M.L., T.C., M.K., B.E.S., C.J.O.); and Departments of Pathology (S.C.S.) and Pharmaceutical Sciences (Y.L.), University of Pittsburgh, Pittsburgh, Pennsylvania
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Stephen C. Strom
Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, Pennsylvania (E.M.L., T.C., M.K., B.E.S., C.J.O.); and Departments of Pathology (S.C.S.) and Pharmaceutical Sciences (Y.L.), University of Pittsburgh, Pittsburgh, Pennsylvania
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Yong Li
Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, Pennsylvania (E.M.L., T.C., M.K., B.E.S., C.J.O.); and Departments of Pathology (S.C.S.) and Pharmaceutical Sciences (Y.L.), University of Pittsburgh, Pittsburgh, Pennsylvania
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Curtis J. Omiecinski
Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, Pennsylvania (E.M.L., T.C., M.K., B.E.S., C.J.O.); and Departments of Pathology (S.C.S.) and Pharmaceutical Sciences (Y.L.), University of Pittsburgh, Pittsburgh, Pennsylvania
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Abstract

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.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This study was supported by a grant from the National Institutes of Health National Institute of General Medicine [Grant GM066411].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    http://dx.doi.org/10.1124/mol.112.080721.

  • ABBREVIATIONS:

    NR
    nuclear receptor
    AF
    activation function
    ANDRO
    5α-androstan-3α-ol
    CAR
    constitutive androstane receptor
    CITCO
    6-(4-chlorophenyl)imidazo[2,1-b]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime
    CMV
    cytomegalovirus
    DAX-1
    dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1
    DBD
    DNA-binding domain
    DMSO
    dimethyl sulfoxide
    CAS
    Chemical Abstract Service
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    HNF4α
    hepatocyte nuclear factor 4α
    LBD
    ligand-binding domain
    LXR
    liver X receptor
    PB
    phenobarbital
    PBREM
    phenobarbital response enhancer module
    RID
    receptor interaction domain
    RXR
    retinoid X receptor
    SHP
    small heterodimer protein
    SRC-1
    steroid receptor coactivator 1
    TSD
    transcription silencing domain
    VP16
    virus protein 16
    XREM
    xenobiotic response enhancer module
    NFDM
    nonfat dried milk
    HRP
    horseradish peroxidase
    TTBS
    Tween Tris-buffered saline.

  • Received June 21, 2012.
  • Accepted August 15, 2012.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 82 (5)
Molecular Pharmacology
Vol. 82, Issue 5
1 Nov 2012
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Research ArticleArticle

DAX-1 Interaction with CAR

Elizabeth M. Laurenzana, Tao Chen, Malavika Kannuswamy, Brian E. Sell, Stephen C. Strom, Yong Li and Curtis J. Omiecinski
Molecular Pharmacology November 1, 2012, 82 (5) 918-928; DOI: https://doi.org/10.1124/mol.112.080721

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Research ArticleArticle

DAX-1 Interaction with CAR

Elizabeth M. Laurenzana, Tao Chen, Malavika Kannuswamy, Brian E. Sell, Stephen C. Strom, Yong Li and Curtis J. Omiecinski
Molecular Pharmacology November 1, 2012, 82 (5) 918-928; DOI: https://doi.org/10.1124/mol.112.080721
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