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The mechanism of heme oxygenase-1 (ho-1) gene activation by 15-deoxy-Δ^12,14-prostaglandin J₂ (15d-PGJ₂) was examined. 15d-PGJ₂ stimulated expression of HO-1 mRNA and protein and of a mouse ho-1 gene promoter/luciferase fusion construct (HO15luc) in a dose-dependent manner in mouse hepatoma (Hepa) cells. HO15luc expression was not effected by troglitazone, a peroxisome proliferator-activated receptor-γ (PPAR-γ) ligand, but induction by 15d-PGJ₂ was abrogated by the antioxidant N-acetylcysteine. The primary 15d-PGJ₂ responsive sequences were localized to a 5′ distal enhancer (E1) and identified as the stress-response element, previously shown to mediate ho-1 activation by several agents, including heme and heavy metals. Treatment of Hepa cells with 15d-PGJ₂ stimulated stress-response element-binding activity as judged by electrophoretic mobility shift assays …