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 degradatio n and has been proposed to play a role in protecting cells against oxi dative stress-related injury. We investigated the induction of heme ox ygenase-1 by the tumor promoter arsenite in a chicken hepatoma cell li ne, LMH. We identified a heme oxygenase-1 promoter-driven luciferase r eporter construct that was highly and reproducibly expressed in respon se to sodium arsenite treatment. This construct was used to investigat e the role of mitogen-activated protein (MAP) kinases in arsenite-medi ated heme oxygenase-1 gene expression. In LMH cells, sodium arsenite, cadmium, and heat shock, but not heme, induced activity of the MAP kin ases extracellular-regulated kinase (ERK), c-Jun N-terminal kinase (JN K), and p38. To examine whether these MAP kinases were involved in med iating heme oxygenase-1 gene expression, we utilized constitutively ac tivated and dominant negative components of the ERK, JNK, and p38 MAP kinase signaling pathways. Involvement of an AP-1 site in arsenite ind uction of heme oxygenase-1 gene expression was studied. We conclude th at the MAP kinases ERK and p38 are involved in the induction of heme o xygenase-1, and that at least one AP-1 element (located - 1576 base pa irs upstream of the transcription start site) is involved in this resp onse.