An Important Role of Nrf2-ARE Pathway in the Cellular Defense Mechanism

Abstract

The antioxidant responsive element (ARE) is a cis-acting regulatory element of genes encoding phase II detoxification enzymes and antioxidant proteins, such as NAD(P)H: quinone oxidoreductase 1, glutathione S-transferases, and glutamate-cysteine ligase. Interestingly, it has been reported that Nrf2 (NF-E2-related factor 2) regulates a wide array of ARE-driven genes in various cell types. Nrf2 is a basic leucine zipper transcription factor, which was originally identified as a binding protein of locus control region of ß-globin gene. The DNA binding sequence of Nrf2 and ARE sequence are very similar, and many studies demonstrated that Nrf2 binds to the ARE sites leading to up-regulation of downstream genes. The function of Nrf2 and its downstream target genes suggests that the Nrf2-ARE pathway is important in the cellular antioxidant defense system. In support of this, many studies showed a critical role of Nrf2 in cellular protection and anti-carcinogenicity, implying that the Nrf2-ARE pathway may serve as a therapeutic target for neurodegenerative diseases and cancers, in which oxidative stress is closely implicated.

Role of oxidative stress in the induction of metallothionein-2A and heme oxygenase-1 gene expression by the antineoplastic agent gallium nitrate in human lymphoma cells

“…Indeed, metallothionein and HO-1 are among a group of Phase II detoxification enzymes and antioxidant proteins that function as a cellular defense mechanism against oxidative stress [39,40]; the expression of HO-1 in response to ROS is regulated by the interaction of transcription factor Nrf-2 with ARE sequences in the promoter regions of their respective genes [36]. Since MAP kinases are known to be involved in the activation of Nrf-2 [31], we examined whether gallium nitrate was signaling through this pathway.…”

“…Studies have indicated that the induction of HO-1 gene expression by MAP kinases is regulated through the activity of Nrf2, a basic leucine zipper transcription factor that interacts with antioxidant response elements (AREs) in the promoter region of the HO-1 gene [31,36]. Under basal conditions, Nrf2 is sequestered in the cytoplasm bound to KEAP-1 (Kelch-like ECHassociating protein 1) which targets it for proteasomal degradation [36].…”

“…Under basal conditions, Nrf2 is sequestered in the cytoplasm bound to KEAP-1 (Kelch-like ECHassociating protein 1) which targets it for proteasomal degradation [36]. In the presence of appropriate signals however, Nrf2 translocates from the cytoplasm to the nucleus to bind to ARE sequences resulting in transcription of the HO-1 gene [31,36]. To determine whether Nrf2 plays a role in gallium-induced HO-1 expression, cells were examined for changes in nuclear Nrf2 levels following exposure to gallium nitrate.…”

Examining the Endogenous Antioxidant Response Through Immunofluorescent Analysis of Nrf2 in Tissue

“…To combat this omnipresent oxidative stress, animal cells have evolved an endogenous antioxidant response. Nuclear factor (erythroid-derived 2) (NF-E2)-related factor 2 (Nrf2), is the key regulator of antioxidant response genes, making it an essential player in this endogenous cellular antioxidant response 1,2,3,4,5,6,7 ). Nrf2 is a member of the Cap 'n' Collar family of transcription factors, which includes Nrf1, Nrf3, p45, Bach1, and Bach2 2 ).…”

“…Nrf2 is a member of the Cap 'n' Collar family of transcription factors, which includes Nrf1, Nrf3, p45, Bach1, and Bach2 2 ). Nrf2 binds the antioxidant responsive element (ARE), also known as the electrophile response element (EpRE)), a cis-acting regulatory element found in the 5′-flanking region of genes encoding enzymes for antioxidant production and of other Nrf2 target genes 2,3,8 ). Genes regulated by Nrf2 include heme oxygenase-1 (HO-1), ubiquitin/PKC-ζ-interacting protein A170, glutathione S-transferases (GST), NAD(P)H quinone oxidoreductase (NQO1), peroxiredoxin 1, catalasc, glutathione peroxidase, superoxide dismutase (SOD), and thioredoxin 1,4,9,10,11,12 ).…”