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Review
, 284 (20), 13291-5

The Nrf2-antioxidant Response Element Signaling Pathway and Its Activation by Oxidative Stress

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Review

The Nrf2-antioxidant Response Element Signaling Pathway and Its Activation by Oxidative Stress

Truyen Nguyen et al. J Biol Chem.

Abstract

A major mechanism in the cellular defense against oxidative or electrophilic stress is activation of the Nrf2-antioxidant response element signaling pathway, which controls the expression of genes whose protein products are involved in the detoxication and elimination of reactive oxidants and electrophilic agents through conjugative reactions and by enhancing cellular antioxidant capacity. At the molecular level, however, the regulatory mechanisms involved in mediating Nrf2 activation are not fully understood. It is well established that Nrf2 activity is controlled, in part, by the cytosolic protein Keap1, but the nature of this pathway and the mechanisms by which Keap1 acts to repress Nrf2 activity remain to be fully characterized and are the topics of discussion in this minireview. In addition, a possible role of the Nrf2-antioxidant response element transcriptional pathway in neuroprotection will also be discussed.

Figures

FIGURE 1.
FIGURE 1.
Regulation of rat GSTA2 and NQO1 gene expression. Induction of these two detoxication enzymes is regulated at the transcriptional level mediated by two distinct enhancers, XRE and ARE, controlled by the AhR and Nrf2, respectively. β-Naphthoflavone (β-NF), 3-methylcholanthrene (3-MC), and benzo(a)pyrene (B(a)P) induce expression of these genes through two different pathways, directly by activating the AhR, which, following dimerizing with the aryl hydrocarbon receptor nuclear translocator (ARNT), binds to the XRE to activate transcription, and indirectly via the Nrf2-ARE pathway following their biotransformation to a reactive intermediate. Nrf2 dimerizes with a basic region-leucine zipper (bZIP) protein and binds to the ARE to activate gene transcription. Induction via the AhR-XRE pathway appears to represent an early mechanism of defense against the eventual metabolic transformation of the xenobiotics to their reactive forms. TCDD, 2,3,7,8-tetraclorodibenzo-p-dioxin.
FIGURE 2.
FIGURE 2.
Nuclear localization of Nrf2 in human umbilical vein endothelial cells. Localization of Nrf2 was performed by immunocytochemistry and confocal microscopy. Nrf2 was stained with an anti-Nrf2 antibody (14) and visualized with a secondary antibody conjugated with Alexa Fluor 488. The nuclei were counterstained with 4′,6-diamidino-2-phenylindole (DAPI), and the F-actin filaments were stained with Alexa Fluor 680-conjugated phalloidin.
FIGURE 3.
FIGURE 3.
Proposed Nrf2-ARE signaling pathway. Nrf2 is expressed constitutively in the cell and translocates directly to the nucleus following its synthesis. Following transactivation of its genes, Nrf2 is targeted for degradation by Keap1 in the nucleus, a process that requires the transient shuttling of Keap1 into this compartment. In cells under stress, stabilization of Nrf2 is thought to be dependent on mechanisms that either prevent or reduce access of Keap1 to Nrf2. This figure was reproduced from Ref. .

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