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Molecular Pharmacology

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Research ArticleArticle

A Novel Nonconsensus Xenobiotic Response Element Capable of Mediating Aryl Hydrocarbon Receptor-Dependent Gene Expression

Gengming Huang and Cornelis J. Elferink
Molecular Pharmacology March 2012, 81 (3) 338-347; DOI: https://doi.org/10.1124/mol.111.075952
Gengming Huang
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Cornelis J. Elferink
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Abstract

The aryl hydrocarbon receptor (AhR) is a mediator of xenobiotic toxicity, best recognized for conveying the deleterious effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure. The AhR functions as a ligand-activated transcription factor that binds to a canonical xenobiotic response element (XRE) in association with the heterodimerization partner, the AhR nuclear translocator (Arnt) protein. However, within the repertoire of AhR target genes identified in recent years, many lack a clearly defined XRE highlighting the growing realization that AhR-mediated gene expression seems to involve additional mechanisms distinct from the well characterized process involving the XRE. The present study characterized a novel nonconsensus XRE (NC-XRE) in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene that recruits a novel protein-DNA complex responsible for TCDD-inducible expression. DNA binding studies and reporter assays identified key residues in the NC-XRE necessary for protein-DNA binding and function, respectively. Functional studies with AhR expression constructs confirm that TCDD-inducibility is AhR-dependent and requires direct AhR-DNA binding to the NC-XRE. Chromatin immunoprecipitation and RNA interference studies reveal that the Arnt protein is not a component of the NC-XRE-bound AhR complex, suggesting that in contrast to the XRE, AhR-dependent gene expression mediated through the NC-XRE may involve a new DNA binding partner.

Footnotes

  • This work was supported by the National Institutes of Environmental Health Sciences [Grants R01-ES07800, P30-ES06676].

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

    http://dx.doi.org/10.1124/mol.111.075952.

  • ABBREVIATIONS:

    PAS
    Per-Arnt-Sim (periodicity/aryl hydrocarbon receptor nuclear translocator/single-minded)
    AhR
    aryl hydrocarbon receptor
    TCDD
    2,3,7,8-tetrachlorodibenzo-p-dioxin
    XRE
    xenobiotic responsive element
    PAI-1
    plasminogen activator inhibitor-1
    Arnt
    aryl hydrocarbon receptor nuclear translocator
    CKO
    conditional knockout
    PAGE
    polyacrylamide gel electrophoresis
    CHX
    cycloheximide
    RT-PCR
    real-time polymerase chain reaction
    CT
    cycle threshold
    ChIP
    chromatin immunoprecipitation
    bp
    base pair(s)
    EMSA
    electrophoretic mobility shift assay
    NC-XRE
    nonconsensus XRE
    MOI
    multiplicity of infection
    GFP
    green fluorescent protein.

  • Received September 20, 2011.
  • Accepted November 23, 2011.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 81 (3)
Molecular Pharmacology
Vol. 81, Issue 3
1 Mar 2012
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Research ArticleArticle

AhR Signaling through a NC-XRE

Gengming Huang and Cornelis J. Elferink
Molecular Pharmacology March 1, 2012, 81 (3) 338-347; DOI: https://doi.org/10.1124/mol.111.075952

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Research ArticleArticle

AhR Signaling through a NC-XRE

Gengming Huang and Cornelis J. Elferink
Molecular Pharmacology March 1, 2012, 81 (3) 338-347; DOI: https://doi.org/10.1124/mol.111.075952
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