Mechanism of sodium arsenite-mediated induction of heme oxygenase-1 in hepatoma cells. Role of mitogen-activated protein kinases.
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.
Elbirt
K K
KK
Department of Biochemistry and Molecular Biology, Howard Hughes Medical Institute, Worcester, Massachusetts 01655, USA. kimberly.gabis@ummed.edu
Whitmarsh
A J
AJ
Davis
R J
RJ
Bonkovsky
H L
HL
D000818:Animals; D018053:Arsenites / Q000494:pharmacology*; D002104:Cadmium / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000096:biosynthesis* / Q000378:metabolism; D006528:Carcinoma, Hepatocellular; D002645:Chickens; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006418:Heme / Q000494:pharmacology; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis*; D051547:Heme Oxygenase-1; D006358:Hot Temperature; D048031:JNK Mitogen-Activated Protein Kinases; D007700:Kinetics; D008113:Liver Neoplasms; D008156:Luciferases / Q000096:biosynthesis; D020928:Mitogen-Activated Protein Kinases; D008969:Molecular Sequence Data; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects; D017670:Sodium Compounds / Q000494:pharmacology*; D016385:TATA Box; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases
D018053:Arsenites; D004791:Enzyme Inhibitors; D005419:Flavonoids; D011993:Recombinant Fusion Proteins; D017670:Sodium Compounds; D018808:Transcription Factor AP-1; D002104:Cadmium; D006418:Heme; C017947:sodium arsenite; D008156:Luciferases; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one