Nrf2 signaling in coordinated activation of antioxidant gene expression

Jaiswal, Anil K.

doi:10.1016/j.freeradbiomed.2004.02.074

Cited by 1,137 publications

(833 citation statements)

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“…c-Jun can form part of the AP-1, StRE [31], and EpRE binding complexes [64] and further, StRE-and EpRE-mediated induction of HO-1 has been shown previously in rat cell lines [31,64,65]. Although no change in total EpRE binding was observed in response to HNE, the EpRE and/ or StRE enhancer elements could still be involved in the increase in HO-1 mRNA via transcription factor complex remodeling [39], specifically through activated c-Jun joining the complex and potentially displacing an inhibitor [66].It has also been shown that Nrf-2 nuclear translocation can be dependent on ERK phosphorylation [43], but other protein kinases may act in place of ERK in Nrf-2 nuclear translocation. The Western data ( Fig.…”

mentioning

confidence: 59%

HNE increases HO-1 through activation of the ERK pathway in pulmonary epithelial cells

Iles

Dickinson

Wigley

et al. 2005

Free Radical Biology and Medicine

101

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Heme oxygenase-1 (HO-1) is a key cytoprotective enzyme and an established marker of oxidative stress. Increased HO-1 expression has been found in the resident macrophages in the alveolar spaces of smokers. The lipid peroxidation product 4-hydroxynonenal (HNE) is also increased in the bronchial and alveolar epithelium in response to cigarette smoke. This suggests a link between a chronic environmental stress, HNE formation, and HO-1 induction. HNE is both an agent of oxidative stress in vivo and a potent cell signaling molecule. We hypothesize that HNE acts as an endogenously produced pulmonary signaling molecule that elicits an adaptive response culminating in the induction of HO-1. Here we demonstrate that HNE increases HO-1 mRNA, protein, and activity in pulmonary epithelial cells and identify ERK as a key pathway involved. Treatment with HNE increased ERK phosphorylation, c-Fos protein, JNK phosphorylation, c-Jun phosphorylation, and AP-1 binding. Whereas inhibiting the ERK pathway with the MEK inhibitor PD98059 significantly decreased HNEmediated ERK phosphorylation, c-Fos protein induction, AP-1 binding, and HO-1 protein induction, inhibition of the ERK pathway had no effect on HNE-induced HO-1 mRNA. This suggests that ERK is involved in the increase in HO-1 through regulation of translation rather than transcription. Keywords 4-Hydroxynonenal; Oxidative stress; HO-1; MAPK signaling; Free radicals Heme oxygenase-1 (HO-1) is an important cytoprotective enzyme and widely accepted marker of oxidative stress. HO-1 catalyzes the first and rate-limiting step in the catabolism of heme, which generates equimolar amounts of biliverdin, ferrous iron, and carbon monoxide [1][2][3]. Although heme is the major substrate of HO-1, a variety of non-heme-containing agents are also strong inducers of HO-1. HO-1 has been shown to respond to a number of proinflammatory cytokines, including TNF-α, . HO-1 is also induced by a variety of agents NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript that cause oxidative stress and/or in response to environmental stress [5][6][7][8]. For example, increased HO-1 expression has recently been found in the alveolar spaces in the resident macrophages of smokers [9]. Once induced, HO-1 provides protection against multiple types of tissue injury [10][11][12][13]; specific to the lung, overexpression of HO-1 in pulmonary epithelial cells has been shown to protect against oxygen toxicity [14]. In contrast, HO-1 deficiency in mice (HO-1 −/− ) increases susceptibility to inflammatory lung injury [15], as does HO-1 deficiency in humans [16]. Although the precise mechanisms by which HO-1 exerts its cytoprotective effects are not known, there is mounting evidence that carbon monoxide plays a key role in this process. For thorough reviews of the recent literature see [17,18].Another characteristic of oxidative stress is the formation of the lipid peroxidation product 4-hydroxy-2-nonenal (HNE). HNE has been shown to increase HO-1 in the cell [19,20], but the mechanism(s...

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mentioning

confidence: 59%

HNE increases HO-1 through activation of the ERK pathway in pulmonary epithelial cells

Iles

Dickinson

Wigley

et al. 2005

Free Radical Biology and Medicine

101

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“…These redox-sensitive EpRE-binding proteins include other members of erythroid 2-related factor (Nrf) family Nrf1 and Nrf3, small Maf protein family members (MafG/K/F), and Jun (c-Jun, JunB, JunD) and Fos family members (c-Fos, FosB, Fra1, Fra2, etc.) (for reviews, see [36,37]). The transcription factors bound to the EpRE in response to stimuli may be cell, inducer, or gene specific.…”

Section: Discussionmentioning

confidence: 99%

“…By using reporter deletion/mutation strategies, we show that the EpRE sequence in the proximal region of GP5 is required for the basal and HNE-induced gene expression. We also demonstrated that NF-E2-related factor 2 (Nrf2), the redox sensitive transcription factors involved in the induction of many EpRE-mediated antioxidant and phase II genes [36,37], is activated by HNE and its recruitment to GP5 EpRE was significantly increased upon HNE exposure. Furthermore, we found that GGT mRNA V-2 is widely expressed in various rat tissues, suggesting the potential role of EpRE/Nrf2 signaling in oxidative stress-mediated GGT induction in these tissues.…”

Section: Introductionmentioning

confidence: 95%

γ-Glutamyl transpeptidase is induced by 4-hydroxynonenal via EpRE/Nrf2 signaling in rat epithelial type II cells

Zhang

Liu

Dickinson

et al. 2006

Free Radical Biology and Medicine

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Abstractγ-Glutamyl transpeptidase (GGT) plays key roles in glutathione homeostasis and metabolism of glutathione S-conjugates. Rat GGT is transcribed via five tandemly arranged promoters into seven transcripts. The transcription of mRNAV is controlled by promoter 5. Previously we found that GGT mRNAV-2 was responsible for the induction of GGT in rat alveolar epithelial cells by 4-hydroxynonenal (HNE). In the current study, the underlying mechanism was investigated. Reporter deletion and mutation analysis demonstrated that an electrophile-response element (EpRE) in the proximal region of GGT promoter 5 (GP5) was responsible for the basal-and HNE-induced promoter activity. Gel-shift assays showed an increased binding activity of GP5 EpRE after HNE exposure. The nuclear content of NF-E2-related factor 2 (Nrf2) was significantly increased by HNE. The recruitment of Nrf2 to GP5 EpRE after HNE treatment was demonstrated by supershift and chromatin immunoprecipitation assays. The tissue expression pattern of GGT mRNA V was previously unknown. Using polymerase chain reaction, we found that GGT mRNAV-2 was expressed in many tissues in rat. Taken together, GGT mRNAV-2 is widely expressed in rat tissues and its basal and HNE-induced expression is mediated through EpRE/Nrf2 signaling.

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“…Nrf2 directly targets a battery of roughly 250 genes responsible for a wide array of cellular antioxidant responses and detoxification processes, e.g. aldo-keto reductase, glutathione S-transferase, heme oxygenase-1, multidrug-resistance associated efflux pumps and NAD(P)H dehydrogenase quinone (NQO)-1 [6,7]. The level of Nrf2 protein is regulated by its inhibitor kelch-like ECH-associated protein (Keap1), and the binding of Keap1 to Nrf2 leads to its degradation in a ubiquitin-dependent manner [7,8].…”

Section: Introductionmentioning

confidence: 99%

miR-214 protects erythroid cells against oxidative stress by targeting ATF4 and EZH2

Gao

Liu

Chen

et al. 2016

Free Radical Biology and Medicine

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Nrf2 signaling in coordinated activation of antioxidant gene expression

Cited by 1,137 publications

References 85 publications

HNE increases HO-1 through activation of the ERK pathway in pulmonary epithelial cells

HNE increases HO-1 through activation of the ERK pathway in pulmonary epithelial cells

γ-Glutamyl transpeptidase is induced by 4-hydroxynonenal via EpRE/Nrf2 signaling in rat epithelial type II cells

miR-214 protects erythroid cells against oxidative stress by targeting ATF4 and EZH2

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