Activation of mitogen-activated protein kinase pathways induces antioxidant response element-mediated gene expression via a Nrf2-dependent mechanism

Antioxidant response element (ARE) regulates the induction of a number of c ellular antioxidant and detoxifying enzymes. However, the signaling pathway s that lead to ARE activation remain unknown. Here, we report that the expr ession of mitogen-activated protein (MAP) kinase/extracellular signal-regul ated kinase kinase kinase 1 (MEKK1), transforming growth factor-beta -activ ated kinase (TAK1), and apoptosis signal-regulating kinase (ASK1) in HepG2 cells activated the ARE reporter gene, whereas the expression of their domi nant-negative mutants impaired ARE activation by the chemicals sodium arsen ite and mercury chloride. Coexpression of downstream kinases, MAP kinase ki nase 4, MAP kinase kinase 6, and c-Jun NH2-terminal kinase-1, but not MAP k inase kinase 3 and p38, augmented ARE activation by MEKK1, TAK1, and ASK1. The coexpression of a basic leucine zipper transcription factor Nrf2 but no t c-Jun also greatly enhanced the activation of reporter gene by MEKK1, TAK 1, and ASK1; however, a dominant-negative mutant of Nrf2 (NF-ES-related fac tor 2) blocked this event. Furthermore, when overexpressed, MEKK1, TAK1, an d ASK1 induced the expression of heme oxygenase-l, a gene regulated by ARE, and the cotransfection with the dominant-negative mutant of Nrf2 abolished the induction. Taken together, these results suggest that MAP kinase pathw ays that are activated by MEKK1, TAK1, and ASK1 may link chemical signals t o Nrf2, leading to the activation of ARE-dependent genes.