Molecular Mechanism of Nrf2 Activation by Oxidative Stress

Abstract

The capacity of cells to maintain homeostasis during oxidative stress resides in activation or induction of protective enzymes. Nuclear-factor-E2-related factor (Nrf)-2 as a member of bZIP transcription factors is expressed in a variety of tissues. Transcriptional activation of antioxidant genes through an antioxidant response element (ARE) is largely dependent upon Nrf2. The genes that contain a functional ARE include those encoding GSTA1, GSTA2, NAD(P)H:quinone reductase, and gamma-glutamylcysteine synthetase heavy and light subunits that play a role in defense against oxidative stress. Previously, we showed that phosphatidylinositol 3-kinase (PI3-kinase) controls nuclear translocation of Nrf2 in response to oxidative stress, which involves rearrangement of actin microfilaments. Now, we report that PI3-kinase is responsible for the rise of cellular Ca(2+), which is requisite for nuclear translocation of Nrf2. Immunocytochemistry and subcellular fractionation analyses revealed that Nrf2 relocated from the cytoplasm to the plasma membrane prior to its nuclear translocation. We further found that CCAAT/enhancer binding protein-beta (C/EBPbeta), peroxisome proliferatoractivated receptor-gamma (PPARgamma), and retinoid X receptor (RXR) heterodimer serve as the activating transcription factors for the phase II gene induction. Hence, PI3-kinase-mediated Nrf2 activation in combination with activating PPARgamma-RXR and C/EBPbeta contributes to antioxidant phase II enzyme induction via coordinate gene transactivation.

Upregulation and Mitochondrial Sequestration of Hemoglobin Occur in Circulating Leukocytes during Critical Illness, Conferring a Cytoprotective Phenotype

“…It is more likely that hemoglobin exerts pleiotropic effects in these cells; it modulates the cellular responses to various oxidants and free radicals (NO, superoxide, H 2 O 2 , peroxynitrite, and so on); hemoglobin, either through acting on membrane receptors or via modulation of intracellular pathways and signal transduction processes, may also regulate the expression of various oxidant-responsive elements (as evidenced, in our study, by the hemoglobin-induced upregulation of HIF-1α and NRF2). Upregulation of both of these factors is known to confer cytoprotection and ischemic/hypoxic preconditioning via a variety of interacting downstream pathways (28,29). Intracellular hemoglobin shows remarkable compartmentalization; it concentrates to the mitochondria, where it shows a particularly close association with mitochondrial complex I.…”

The Tryptophan Metabolite 3-Hydroxyanthranilic Acid Plays Anti-Inflammatory and Neuroprotective Roles During Inflammation

“…10,68,69 Transcription of the HO-1 gene is under the control of antioxidant response element, which is activated by the transcription factor, nuclear factor erythroid-2-related factor 2 (Nrf2). Activation of Nrf2 is typically induced by oxidative stress 70,71 and nitrosative stress (nitric oxide). 72 In this regard, the low expression of HO-1 in human microglia may in part be due to their inability to express iNOS.…”

Molecular characterization and functions of zebrafish ABCC2 in cellular efflux of heavy metals

“…Furthermore, heavy metals such as lead, cadmium and mercury may cause an increase in production of reactive oxygen species (ROS) (Ercal et al, 2001) and expression of ABCC2 has been demonstrated to be associated with elevated cellular ROS (Payen et al, 2001). The Nrf2 (nuclear factor-erythroid 2 p45-related factor 2) transcription factor, which binds the ARE sequences (antioxidant-response element; also named electrophile response element, EPRE) and regulates a battery of detoxifying and antioxidant genes in response to oxidative stress (Adachi et al, 2007;Kang et al, 2005) may be involved in the induction of abcc2 gene by these metals, since previous studies have demonstrated the existence of ARE elements in the promoters of human and mouse Abcc2 gene (Tanaka et al, 1999;Vollrath et al, 2006) and the involvement of ARE-Nrf2 pathway in the induction of Abcc2 gene by several xenobiotics (Vollrath et al, 2006). Therefore, it is of great interest to further study mechanisms underlying the tissuespecific expressing and the induction of zebrafish abcc2 gene by mercury and lead.…”