Mechanism of sodium arsenite-mediated induction of heme oxygenase-1 in hepatoma cells. Role of mitogen-activated protein kinases
Department of Biochemistry and Molecular Biology; Howard Hughes Medical Institute and Program in Molecular Medicine
Animals; Arsenites; Cadmium; Calcium-Calmodulin-Dependent Protein Kinases; Carcinoma, Hepatocellular; Chickens; Enzyme Induction; Enzyme Inhibitors; Flavonoids; Gene Expression Regulation, Neoplastic; Heat; Heme; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; 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
Life Sciences | Medicine and Health Sciences
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.
DOI of Published Version
J Biol Chem. 1998 Apr 10;273(15):8922-31.
The Journal of biological chemistry
Elbirt, Kimberly K.; Whitmarsh, Alan J.; Davis, Roger J.; and Bonkovsky, Herbert L., "Mechanism of sodium arsenite-mediated induction of heme oxygenase-1 in hepatoma cells. Role of mitogen-activated protein kinases" (1998). Open Access Articles. 780.