Transcription Factor Nrf2 Coordinately Regulates a Group of Oxidative Stress-inducible Genes in Macrophages

Abstract

Electrophiles and reactive oxygen species have been implicated in the pathogenesis of many diseases. Transcription factor Nrf2 was recently identified as a general regulator of one defense mechanism against such havoc. Nrf2 regulates the inducible expression of a group of detoxication enzymes, such as glutathione Stransferase and NAD(P)H:quinone oxidoreductase, via antioxidant response elements. Using peritoneal macrophages from Nrf2-deficient mice, we show here that Nrf2 also controls the expression of a group of electrophileand oxidative stress-inducible proteins and activities, which includes heme oxygenase-1, A170, peroxiredoxin MSP23, and cystine membrane transport (system x c Ϫ ) activity. The response to electrophilic and reactive oxygen species-producing agents was profoundly impaired in Nrf2-deficient cells. The lack of induction of system x c Ϫ activity resulted in the minimum level of intracellular glutathione, and Nrf2-deficient cells were more sensitive to toxic electrophiles. Several stress agents induced the DNA binding activity of Nrf2 in the nucleus without increasing its mRNA level. Thus Nrf2 regulates a wideranging metabolic response to oxidative stress.

Flunarizine induces Nrf2-mediated transcriptional activation of heme oxygenase-1 in protection of auditory cells from cisplatin

“…Many studies have reported that HO-1 expression is mainly regulated by Nrf2-dependent ARE activation in several cell types. [44][45][46] Studies of the ectopic expression of Nrf2 and siRNA constructs of Nrf2 and HO-1 further confirmed that the protective effect of flunarizine is indeed through Nrf2/HO-1 in cisplatin-treated cells. Our results also suggest that the AREdriven upregulation of HO-1 gene expression after treatment with flunarizine was mediated by nuclear translocation of Nrf2, not by de novo synthesis of Nrf2 in HEI-OC1.…”

Heme: a versatile signaling molecule controlling the activities of diverse regulators ranging from transcription factors to MAP kinases

“…The Bach1-Maf heterodimers bind to the Maf recognition element (MARE) in the regulatory region of its target genes [72,[74][75][76][77]. MAREs are found in the regulatory regions of genes involved in heme metabolism, such as oxidative stress response genes, globin genes, heme oxygenase-1 and erythroid-specific ALAS [72,[78][79][80][81]. It has been suggested that the transcription of genes possessing MAREs is regulated via a balance between transcriptional activation and repression [22,80].…”

Role of Nrf2 Dysfunction in Uremia-Associated Intestinal Inflammation and Epithelial Barrier Disruption

“…Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that plays a central role in the regulation of antioxidant and phase 2 detoxifying enzymes and related proteins [27,28]. In the cytoplasm, Keap1 (Kelchlike ECH-associated protein 1) binds to Nrf2 and facilitates its ubiquitination and thereby prevents its translocation to the nucleus.…”