Identification of the NF-E2-related Factor-2-dependent Genes Conferring Protection against Oxidative Stress in Primary Cortical Astrocytes Using Oligonucleotide Microarray Analysis*

By Jong‐Min Lee, M. Calkins, K. Chan, Y. Kan, Jeffrey A. Johnson. Journal of Biological Chemistry, 2003

808 citations recorded by the source corpus.

The antioxidant responsive element (ARE) mediates transcriptional regulation of phase II detoxification enzymes and antioxidant proteins such as NAD(P)H:quinone oxidoreductase (NQO1), glutathione S-transferases, and glutamate-cysteine ligase. In this study, we demonstrate that NF-E2-related factor-2 (Nrf2) plays a major role in transcriptional activation of ARE-driven genes and identify Nrf2-dependent genes by oligonucleotide microarray analysis using primary cortical astrocytes from Nrf2+/+ and Nrf2−/− mice. Nrf2−/−astrocytes had decreased basal NQO1 activity and no induction bytert-butylhydroquinone compared with Nrf2+/+ astrocytes. Similarly, both basal and induced levels of human NQO1-ARE-luciferase expression in Nrf2−/− astrocytes were significantly lower than in Nrf2+/+ astrocytes. Furthermore, human NQO1-ARE-luciferase expression in Nrf2−/−astrocytes was restored by overexpression of Nrf2, whereas ARE activation in Nrf2+/+ astrocytes was completely blocked by dominant-negative Nrf2. In addition, we observed that Nrf2-dependent genes protected primary astrocytes from H2O2- or platelet-activating factor-induced apoptosis. In support of these observations, we identified Nrf2-dependent genes encoding detoxification enzymes, glutathione-related proteins, antioxidant proteins, NADPH-producing enzymes, and anti-inflammatory genes using oligonucleotide microarrays. Proteins within these functional categories are vital to the maintenance and responsiveness of a cell defense system, suggesting that an orchestrated change in gene expression via Nrf2 and the ARE gives a synergistic protective effect against oxidative stress.

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Citations in the corpus

Silymarin as a Natural Antioxidant: An Overview of the Current Evidence and Perspectives (2015, unknown): “Therefore, an orchestrated change in gene expression via Nrf2 and the ARE is responsible for a synergistic protective effect against oxidative stress [168].”
Transcriptional Regulation by Nrf2 (2017, background): “regulation of the principal NADPH-generating enzymes: glucose-6-phosphate dehydrogenase (G6pd), 6-phosphogluconate dehydrogenase (Pgd), isocitrate dehydrogenase 1 (Idh1), and malic enzyme 1 (Me1), as shown in primary cortical astrocytes (91), lung cancer cells (107), mouse small intestine (164), and”
Mechanisms of activation of the transcription factor Nrf2 by redox stressors, nutrient cues, and energy status and the pathways through which it attenuates degenerative disease (2015, unknown): “The main enzymes involved in NADPH production, ME1, IDH1, G6PD, and PGD, are all regulated in part by Nrf2 [61, 115, 121, 375, 376], with low levels of the cofactor seen in Nrf2−/− mice and correspondingly high levels in mice with hepatocyte-specific Keap1 knockout [115].”
Keap1 Is a Redox-Regulated Substrate Adaptor Protein for a Cul3-Dependent Ubiquitin Ligase Complex (2004, unknown): “3 g, lanes 2 to 5), and Cul3(1-380) (from 0.”
Mechanistic Studies of the Nrf2-Keap1 Signaling Pathway (2006, background): “…can be classified into categories according to their functions: cellular redox homeostasis, cell growth and apoptosis, inflammatory response, and the ubiquitin-mediated degradation pathway (Thimmulappa et al., 2002; Kwak et al., 2003; Lee et al., 2003; Rangasamy et al., 2004; Cho et al., 2005).”
The Role of the Reactive Oxygen Species and Oxidative Stress in the Pathomechanism of the Age-Related Ocular Diseases and Other Pathologies of the Anterior and Posterior Eye Segments in Adults (2016, background): “Nrf2 shows a high affinity to the antioxidant response element (ARE), which is involved in transcriptional activation of genes encoding proteins important for the protection against the oxidative stress, including peroxiredoxin, glutathione Stransferases, heme oxygenase-1 (HO-1), thioredoxin reducta”
Cytokines in Radiobiological Responses: A Review (2012, unknown): “binds the antioxidant response element (ARE) in the nucleus to transcribe numerous Phase II detoxification enzymes and antioxidant proteins (99).”