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

Rong Yu, Chi Chen, Yin Yuan Mo, Vidya Hebbar, Edward D. Owuor, Tse Hua Tan, A. N.Tony Kong

Research output: Contribution to journalArticlepeer-review

288 Scopus citations

Abstract

Antioxidant response element (ARE) regulates the induction of a number of cellular antioxidant and detoxifying enzymes. However, the signaling pathways that lead to ARE activation remain unknown. Here, we report that the expression of mitogen-activated protein (MAP) kinase/extracellular signal-regulated kinase kinase kinase 1 (MEKK1), transforming growth factor-β-activated kinase (TAK1), and apoptosis signal-regulating kinase (ASK1) in HepG2 cells activated the ARE reporter gene, whereas the expression of their dominant-negative mutants impaired ARE activation by the chemicals sodium arsenite and mercury chloride. Coexpression of downstream kinases, MAP kinase kinase 4, MAP kinase kinase 6, and c-Jun NH2-terminal kinase-1, but not MAP kinase kinase 3 and p38, augmented ARE activation by MEKK1, TAK1, and ASK1. The coexpression of a basic leucine zipper transcription factor Nrf2 but not c-Jun also greatly enhanced the activation of reporter gene by MEKK1, TAK1, and ASK1; however, a dominant-negative mutant of Nrf2 (NF-E2-related factor 2) blocked this event. Furthermore, when overexpressed, MEKK1, TAK1, and ASK1 induced the expression of heme oxygenase-1, 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 pathways that are activated by MEKK1, TAK1, and ASK1 may link chemical signals to Nrf2, leading to the activation of ARE-dependent genes.

Original languageEnglish (US)
Pages (from-to)39907-39913
Number of pages7
JournalJournal of Biological Chemistry
Volume275
Issue number51
DOIs
StatePublished - Dec 22 2000

Fingerprint Dive into the research topics of 'Activation of mitogen-activated protein kinase pathways induces antioxidant response element-mediated gene expression via a Nrf2-dependent mechanism'. Together they form a unique fingerprint.

Cite this