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Research ArticleArticle

Negative Regulation of the Rat GlutathioneS-Transferase A2 Gene by Glucocorticoids Involves a Canonical Glucocorticoid Consensus Sequence

K. Cameron Falkner, Thomas H. Rushmore, Mark W. Linder and Russell A. Prough
Molecular Pharmacology June 1998, 53 (6) 1016-1026;
K. Cameron Falkner
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Thomas H. Rushmore
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Mark W. Linder
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Russell A. Prough
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Abstract

Glucocorticoids (GCs) repress both basal and polyaromatic hydrocarbon-induced expression of the glutathioneS-transferase Ya1 gene (gstA2) in isolated rat hepatocytes and rat liverin vivo. Transient transfection experiments with HepG2 cells were used to identify GC-responsive elements (GREs). With cotransfected GC receptor, chloramphenicol acetyltransferase (CAT) constructs containing a palindromic GRE (pGRE) and three GRE hexanucleotide half-sites between −1.6 and −1.1 kb of the 5′-flanking region of gstA2 were repressed >50% by GC when induced with polyaromatic hydrocarbon. This pGRE, if either mutated or deleted, significantly reduces GC responsiveness of the gene to 20–30%; no effect of GC was observed with CAT constructs containing −1.15 kb of the 5′-flanking region. The dexamethasone concentration dependence of the repression was consistent with involvement of the GC receptor and was antagonized by RU38486. Electrophoretic mobility shift assays demonstrated that pGRE formed a specific DNA/protein complex, which was prevented by the addition of excess unlabeled or mouse mammary tumor virus GRE but not by unrelated or mutated gstA2 GRE double-stranded oligonucleotides. This complex was supershifted by incubation of nuclear extracts containing GC receptor with anti-GC receptor globulins. Constructs containing multiple copies of pGRE sequence were either nonresponsive or positively responsive (three copies) to GC. Luciferase constructs containing −1.62 to −1.03 kb of the 5′-flanking region also were regulated positively by GC. Chimeric GC-peroxisome proliferator activated receptor activated the constructs that were positively responsive to GC but did not mediate the negative effect in constructs containing 1.6 kb of 5′-flanking region. We conclude that pGRE and half-site GREs of gstA2participate in regulation of this gene; however, a second unidentified responsive element must exist between −1.03 and −0.164 kb, resulting in repression of gstA2 expression.

Footnotes

  • Send reprint requests to: Russell A. Prough, Ph.D., Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Louisville, KY 40292. E-mail:raprou01{at}ulkyvm.louisville.edu

  • This work was supported in part by National Institutes of Environmental Health Sciences Grant ES04244.

  • Abbreviations:
    gstA2
    glutathioneS-transferase 1 (Ya1) subunit gene
    AHRRE
    aryl hydrocarbon receptor response element
    AHR
    aryl hydrocarbon receptor
    ARE
    antioxidant response element
    BA
    1,2-benzanthracene
    CAT
    chloramphenicol acetyltransferase
    C/EBP
    CCAAT/enhancer binding protein
    bp
    base pair(s)
    CMV
    cytomegalovirus
    DEX
    dexamethasone
    GC
    glucocorticoid
    GRE
    hexonucleotide glucocorticoid response element [TGT(T/C)CT]
    PCR
    polymerase chain reaction
    pGRE
    palindromic glucocorticoid response element
    HNF
    hepatic nuclear factor
    PAH
    polyaromatic hydrocarbon
    PPAR
    peroxisome proliferator activated receptor
    MMTV
    mouse mammary tumor virus
    • Received February 4, 1998.
    • Accepted February 19, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 53 (6)
Molecular Pharmacology
Vol. 53, Issue 6
1 Jun 1998
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Research ArticleArticle

Negative Regulation of the Rat GlutathioneS-Transferase A2 Gene by Glucocorticoids Involves a Canonical Glucocorticoid Consensus Sequence

K. Cameron Falkner, Thomas H. Rushmore, Mark W. Linder and Russell A. Prough
Molecular Pharmacology June 1, 1998, 53 (6) 1016-1026;

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Research ArticleArticle

Negative Regulation of the Rat GlutathioneS-Transferase A2 Gene by Glucocorticoids Involves a Canonical Glucocorticoid Consensus Sequence

K. Cameron Falkner, Thomas H. Rushmore, Mark W. Linder and Russell A. Prough
Molecular Pharmacology June 1, 1998, 53 (6) 1016-1026;
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