Novel insights into the regulation of antioxidant-response-elementmediated gene expression by electrophiles: induction of the transcriptional repressor BACH1 by Nrf2

Abstract

A central mechanism in cellular defence against oxidative or electrophilic stress is mediated by transcriptional induction of genes via the ARE (antioxidant-response element), 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 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 (cap'n'collar 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 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.

Hydrogen sulfide preconditions thedb/dbdiabetic mouse heart against ischemia-reperfusion injury by activating Nrf2 signaling in an Erk-dependent manner

“…For instance, Bach1 directly competes with Nrf2 in binding to the promoter of ARE-related genes leading to the negative regulation of Nrf2 signaling (14,15). Our initial analysis found that the nuclear expression of Bach1 was increased in the diabetic heart, suggesting that it may contribute to the impairment of Nrf2 signaling in response to Na 2 S as it relates to HO-1.…”

Nrf2 Pathway in Age-Related Neurological Disorders: Insights into MicroRNAs

“…Notably, Bach1 itself is a target gene of Nrf2, thus generating a negative feedback circuit for ARE-dependent gene transcription. This cross-talk could be essential to produce the correct level of antioxidant genes under stress [71]. Very recently, it has been reported that Nrf2 directly interacts with the subunit MED16 of the Mediator complex.…”

Wearing Red for Signaling: The Heme-Bach Axis in Heme Metabolism, Oxidative Stress Response and Iron Immunology

“…Other MARE-binding factors may also transactivate Bach1. Indeed, Nrf2 induces the expression of Bach1, thus generating a negative feedback regulation of the Nrf2 response (Jyrkkanen et al 2011).…”

“…Nrf2 activates the expression of Bach1, which appears to constitute a negative feedback loop intended to prevent the overexpression of HO-1 following the resolution of oxidative stress (Jyrkkanen et al 2011). Other transcription factors, such as NF-kB also play roles in the basal and inducible expression of HO-1, depending on the cell type and inducing signal/stressor (Paine et al 2010).…”