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Research ArticleArticle

Activator Protein-1 Regulation of Murine Aldehyde Dehydrogenase 1a1

N. L. Makia, I. Amunom, K. C. Falkner, D. J. Conklin, S. Surapureddi, J. A. Goldstein and R. A. Prough
Molecular Pharmacology October 2012, 82 (4) 601-613; DOI: https://doi.org/10.1124/mol.112.078147
N. L. Makia
Departments of Biochemistry and Molecular Biology (N.L.M., I.A., R.A.P.), Medicine/Gastroenterology, Hepatology, and Nutrition (K.C.F.), and Medicine/Cardiovascular Medicine and Diabetes and Obesity Center (D.J.C.), University of Louisville School of Medicine, Louisville, Kentucky; and Human Metabolism Group, National Institutes of Environmental Health Sciences, Research Triangle Park, North Carolina, North Carolina (S.S., J.A.G.)
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I. Amunom
Departments of Biochemistry and Molecular Biology (N.L.M., I.A., R.A.P.), Medicine/Gastroenterology, Hepatology, and Nutrition (K.C.F.), and Medicine/Cardiovascular Medicine and Diabetes and Obesity Center (D.J.C.), University of Louisville School of Medicine, Louisville, Kentucky; and Human Metabolism Group, National Institutes of Environmental Health Sciences, Research Triangle Park, North Carolina, North Carolina (S.S., J.A.G.)
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K. C. Falkner
Departments of Biochemistry and Molecular Biology (N.L.M., I.A., R.A.P.), Medicine/Gastroenterology, Hepatology, and Nutrition (K.C.F.), and Medicine/Cardiovascular Medicine and Diabetes and Obesity Center (D.J.C.), University of Louisville School of Medicine, Louisville, Kentucky; and Human Metabolism Group, National Institutes of Environmental Health Sciences, Research Triangle Park, North Carolina, North Carolina (S.S., J.A.G.)
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D. J. Conklin
Departments of Biochemistry and Molecular Biology (N.L.M., I.A., R.A.P.), Medicine/Gastroenterology, Hepatology, and Nutrition (K.C.F.), and Medicine/Cardiovascular Medicine and Diabetes and Obesity Center (D.J.C.), University of Louisville School of Medicine, Louisville, Kentucky; and Human Metabolism Group, National Institutes of Environmental Health Sciences, Research Triangle Park, North Carolina, North Carolina (S.S., J.A.G.)
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S. Surapureddi
Departments of Biochemistry and Molecular Biology (N.L.M., I.A., R.A.P.), Medicine/Gastroenterology, Hepatology, and Nutrition (K.C.F.), and Medicine/Cardiovascular Medicine and Diabetes and Obesity Center (D.J.C.), University of Louisville School of Medicine, Louisville, Kentucky; and Human Metabolism Group, National Institutes of Environmental Health Sciences, Research Triangle Park, North Carolina, North Carolina (S.S., J.A.G.)
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J. A. Goldstein
Departments of Biochemistry and Molecular Biology (N.L.M., I.A., R.A.P.), Medicine/Gastroenterology, Hepatology, and Nutrition (K.C.F.), and Medicine/Cardiovascular Medicine and Diabetes and Obesity Center (D.J.C.), University of Louisville School of Medicine, Louisville, Kentucky; and Human Metabolism Group, National Institutes of Environmental Health Sciences, Research Triangle Park, North Carolina, North Carolina (S.S., J.A.G.)
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R. A. Prough
Departments of Biochemistry and Molecular Biology (N.L.M., I.A., R.A.P.), Medicine/Gastroenterology, Hepatology, and Nutrition (K.C.F.), and Medicine/Cardiovascular Medicine and Diabetes and Obesity Center (D.J.C.), University of Louisville School of Medicine, Louisville, Kentucky; and Human Metabolism Group, National Institutes of Environmental Health Sciences, Research Triangle Park, North Carolina, North Carolina (S.S., J.A.G.)
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Abstract

Previously we demonstrated that aldehyde dehydrogenase (ALDH) 1a1 is the major ALDH expressed in mouse liver and is an effective catalyst in metabolism of lipid aldehydes. Quantitative real-time polymerase chain reaction analysis revealed a ≈2.5- to 3-fold induction of the hepatic ALDH1A1 mRNA in mice administered either acrolein (5 mg/kg acrolein p.o.) or butylated hydroxylanisole (BHA) (0.45% in the diet) and of cytosolic NAD+-dependent ALDH activity. We observed ≈2-fold increases in ALDH1A1 mRNA levels in both Nrf2(+/+) and Nrf2(−/−) mice treated with BHA compared with controls, suggesting that BHA-induced expression is independent of nuclear factor E2-related factor 2 (Nrf2). The levels of activator protein-1 (AP-1) mRNA and protein, as well as the amount of phosphorylated c-Jun were significantly increased in mouse liver or Hepa1c1c7 cells treated with either BHA or acrolein. With use of luciferase reporters containing the 5′-flanking sequence of Aldh1a1 (−1963/+27), overexpression of c-Jun resulted in an ≈4-fold induction in luciferase activity, suggesting that c-Jun transactivates the Aldh1a1 promoter as a homodimer and not as a c-Jun/c-Fos heterodimer. Promoter deletion and mutagenesis analyses demonstrated that the AP-1 site at position −758 and possibly −1069 relative to the transcription start site was responsible for c-Jun-mediated transactivation. Electrophoretic mobility shift assay analysis with antibodies against c-Jun and c-Fos showed that c-Jun binds to the proximal AP-1 site at position −758 but not at −1069. Recruitment of c-Jun to this proximal AP-1 site by BHA was confirmed by chromatin immunoprecipitation analysis, indicating that recruitment of c-Jun to the mouse Aldh1a1 gene promoter results in increased transcription. This mode of regulation of an ALDH has not been described before.

Footnotes

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

  • This work was supported in part by the National Institutes of Health National Heart, Lung, and Blood Institute [Grant HL89380] (to D.J.C.); the National Institutes of Health National Institute for Environmental Health Sciences [Grant ES11860]; and the Preston Pope Joyes Research Endowment.

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

    http://dx.doi.org/10.1124/mol.112.078147.

  • ABBREVIATIONS:

    ALDH
    aldehyde dehydrogenase
    RA
    retinoic acid
    Nrf2
    nuclear factor E2-related factor 2
    AP-1
    activator protein 1
    Keap-1/keap-1
    Ketch-like ECH-associated protein 1
    ARE
    antioxidant response element
    BHA
    BHA, tert-butylated hydroxyanisole
    JNK
    c-Jun NH2-terminal kinase
    MEK
    mitogen-activated protein kinase kinase
    OA
    okadaic acid
    SP600125
    1,9-pyrazoloanthrone
    PD98059
    2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
    WT
    wild type
    SFN
    sulforaphane
    TRE
    TPA response element
    q
    quantitative
    RT
    real-time
    PCR
    polymerase chain reaction
    JNK
    c-Jun NH2-terminal kinase
    bp
    base pair(s)Y
    DMEM
    Dulbecco's modified Eagle's medium
    FBS
    fetal bovine serum
    DMSO
    dimethyl sulfoxide
    PBS
    phosphate-buffered saline
    EMSA
    electrophoretic mobility shift assay
    ChIP
    chromatin immunoprecipitation assay
    ANOVA
    analysis of variance
    MAPK
    mitogen-activated protein kinase
    kd
    knockdown.

  • Received February 7, 2012.
  • Accepted June 26, 2012.
  • U.S. Government work not protected by U.S. copyright
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Molecular Pharmacology: 82 (4)
Molecular Pharmacology
Vol. 82, Issue 4
1 Oct 2012
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Research ArticleArticle

AP-1 Regulation of Murine Aldehyde Dehydrogenase 1a1

N. L. Makia, I. Amunom, K. C. Falkner, D. J. Conklin, S. Surapureddi, J. A. Goldstein and R. A. Prough
Molecular Pharmacology October 1, 2012, 82 (4) 601-613; DOI: https://doi.org/10.1124/mol.112.078147

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Research ArticleArticle

AP-1 Regulation of Murine Aldehyde Dehydrogenase 1a1

N. L. Makia, I. Amunom, K. C. Falkner, D. J. Conklin, S. Surapureddi, J. A. Goldstein and R. A. Prough
Molecular Pharmacology October 1, 2012, 82 (4) 601-613; DOI: https://doi.org/10.1124/mol.112.078147
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