Mechanism of sodium arsenite-mediated induction of heme oxygenase-1 in hepatoma cells. Role of mitogen-activated protein kinases

K K Elbirt, A J Whitmarsh, R J Davis, H L Bonkovsky

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    Heme oxygenase-1 is an inducible enzyme that catalyzes heme degradation and has been proposed to play a role in protecting cells against oxidative stress-related injury. We investigated the induction of heme oxygenase-1 by the tumor promoter arsenite in a chicken hepatoma cell line, LMH. We identified a heme oxygenase-1 promoter-driven luciferase reporter construct that was highly and reproducibly expressed in response to sodium arsenite treatment. This construct was used to investigate the role of mitogen-activated protein (MAP) kinases in arsenite-mediated heme oxygenase-1 gene expression. In LMH cells, sodium arsenite, cadmium, and heat shock, but not heme, induced activity of the MAP kinases extracellular-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38. To examine whether these MAP kinases were involved in mediating heme oxygenase-1 gene expression, we utilized constitutively activated and dominant negative components of the ERK, JNK, and p38 MAP kinase signaling pathways. Involvement of an AP-1 site in arsenite induction of heme oxygenase-1 gene expression was studied. We conclude that the MAP kinases ERK and p38 are involved in the induction of heme oxygenase-1, and that at least one AP-1 element (located -1576 base pairs upstream of the transcription start site) is involved in this response.

    Original languageEnglish
    Pages (from-to)8922-31
    Number of pages10
    JournalJournal of Biological Chemistry
    Issue number15
    Publication statusPublished - 10 Apr 1998


    • Animals
    • Arsenites
    • Cadmium
    • Calcium-Calmodulin-Dependent Protein Kinases
    • Carcinoma, Hepatocellular
    • Chickens
    • Enzyme Induction
    • Enzyme Inhibitors
    • Flavonoids
    • Gene Expression Regulation, Neoplastic
    • Heme
    • Heme Oxygenase (Decyclizing)
    • Heme Oxygenase-1
    • Hot Temperature
    • JNK Mitogen-Activated Protein Kinases
    • Kinetics
    • Liver Neoplasms
    • Luciferases
    • Mitogen-Activated Protein Kinases
    • Molecular Sequence Data
    • Recombinant Fusion Proteins
    • Signal Transduction
    • Sodium Compounds
    • TATA Box
    • Transcription Factor AP-1
    • Transcription, Genetic
    • Transfection
    • Tumor Cells, Cultured
    • p38 Mitogen-Activated Protein Kinases


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