Novel insights into the regulation of the antioxidant response element mediated gene expression by electrophiles: induction of the transcriptional repressor BACH1 by NRF2
Résumé
A central mechanism in cellular defence against oxidative or electrophilic stress is mediated by transcriptional induction of genes via the Antioxidant Response Element (ARE), a cis-acting sequence present in the regulatory regions of genes involved in the detoxification and elimination of reactive oxidants and electrophiles. The ARE binds different basic-region leucine zipper (bZIP) transcription factors, most notably NF-E2 related factor-2 (Nrf2) that functions as a transcriptional activator via heterodimerization with small Maf proteins. While the ARE activation by Nrf2 is relatively well understood, the mechanisms by which ARE mediated signalling is downregulated is poorly known. Transcription factor BACH1 (BTB and CNC homology 1) binds to ARE-like sequences, functioning as a transcriptional repressor in a subset of ARE-regulated genes thus antagonizing the activator function of Nrf2. Herein, we demonstrate that BACH1 itself is regulated by Nrf2 as it is induced by Nrf2 overexpression and by Nrf2 activating agents in an Nrf2-dependent manner. Furthermore, a functional ARE site was identified at +1411 from the transcription start site of transcript variant 2 of BACH1. We conclude that BACH1 is a bona fide Nrf2 target gene, and that induction of BACH1 by Nrf2 may serve as a feedback inhibitory mechanism for ARE-mediated gene regulation.
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