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>Novel insights into the regulation of antioxidant-response-elementmediated gene expression by electrophiles: induction of the transcriptional repressor BACH1 by Nrf2
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Novel insights into the regulation of antioxidant-response-elementmediated gene expression by electrophiles: induction of the transcriptional repressor BACH1 by Nrf2
pA central mechanism in cellular defence against oxidative or electrophilic stress is mediated by transcriptional induction of genes via the ARE (antioxidant-response element), a icis/i-acting sequence present in the regulatory regions of genes involved in the detoxification and elimination of reactive oxidants and electrophiles. The ARE binds different bZIP (basic-region leucine zipper) transcription factors, most notably Nrf2 (nuclear factor-erythroid 2-related factor 2) that functions as a transcriptional activator via heterodimerization with small Maf proteins. Although ARE activation by Nrf2 is relatively well understood, the mechanisms by which ARE-mediated signalling is down-regulated are poorly known. Transcription factor BACH1 [BTB (broad-complex, tramtrack and bric-a-brac) and CNC (cap9n9collar protein) 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. In the present study, we have demonstrated that iBACH1/i 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 iBACH1/i. We conclude that iBACH1/i is a ibona fide/i Nrf2 target gene and that induction of iBACH1/i by Nrf2 may serve as a feedback-inhibitory mechanism for ARE-mediated gene regulation./p
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