Nrf2, a Cap'n'Collar Transcription Factor, Regulates Induction of the Heme Oxygenase-1 Gene

Alam, Jawed; Stewart, Daniel P.; Touchard, Cheri L.; Boinapally, Sujji; Choi, Augustine M.K.; Cook, Julia

doi:10.1074/jbc.274.37.26071

Cited by 1,177 publications

(891 citation statements)

References 41 publications

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“…The molecular basis for initiating this antioxidant defense mechanism is the transcriptional activation of the HO-1 gene by a series of ARE in its promoter (11,47). It has now been established that the transcription factor Nrf-2 is involved in ARE activation in vivo and in vitro (50,51). Not only have we confirmed that ARE is involved in activation of the HO-1 promoter by aromatic and polar DEP chemicals in macrophages (11), but we also demonstrate exquisite sensitivity of HO-1 to oxidative stress in epithelial cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

Comparison of the Pro-Oxidative and Proinflammatory Effects of Organic Diesel Exhaust Particle Chemicals in Bronchial Epithelial Cells and Macrophages

Wang

Oberley

et al. 2002

The Journal of Immunology

288

231

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Inhaled diesel exhaust particles (DEP) exert proinflammatory effects in the respiratory tract. This effect is related to the particle content of redox cycling chemicals and is involved in the adjuvant effects of DEP in atopic sensitization. We demonstrate that organic chemicals extracted from DEP induce oxidative stress in normal and transformed bronchial epithelial cells, leading to the expression of heme oxygenase 1, activation of the c-Jun N-terminal kinase cascade, IL-8 production, as well as induction of cytotoxicity. Among these effects, heme oxygenase 1 expression is the most sensitive marker for oxidative stress, while c-Jun N-terminal kinase activation and induction of apoptosis-necrosis require incremental amounts of the organic chemicals and increased levels of oxidative stress. While a macrophage cell line (THP-1) responded in similar fashion, epithelial cells produced more superoxide radicals and were more susceptible to cytotoxic effects than macrophages. Cytotoxicity is the result of mitochondrial damage, which manifests as ultramicroscopic changes in organelle morphology, a decrease in the mitochondrial membrane potential, superoxide production, and ATP depletion. Epithelial cells also differ from macrophages in not being protected by a thiol antioxidant, N-acetylcysteine, which effectively protects macrophages against cytotoxic DEP chemicals. These findings show that epithelial cells exhibit a hierarchical oxidative stress response that differs from that of macrophages by more rapid transition from cytoprotective to cytotoxic responses. Moreover, epithelial cells are not able to convert N-acetylcysteine to cytoprotective glutathione.

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Section: Discussionmentioning

confidence: 99%

Comparison of the Pro-Oxidative and Proinflammatory Effects of Organic Diesel Exhaust Particle Chemicals in Bronchial Epithelial Cells and Macrophages

Wang

Oberley

et al. 2002

The Journal of Immunology

288

231

View full text Add to dashboard Cite

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“…Biliverdin in the presence of biliverdin reductase gets reduced to bilirubin, 38 which possesses antioxidative properties. 38 In addition, innate immunity and wound healing processes may be modulated by the up-regulation of HO-1 by Nrf2. 39 NQO1 catalyzes the twoelectron reduction of highly reactive quinones to hydroquinones.…”

Section: Nrf2 In Cellular Redox Homeostasismentioning

confidence: 99%

Nuclear Factor–Erythroid-2–Related Factor 2 in Aging and Lung Fibrosis

Swamy

Rajasekaran

Thannickal

2016

The American Journal of Pathology

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Aging and age-related diseases have been associated with elevated oxidative stress, which may be related to increased production of reactive species and/or a deficiency in antioxidant defenses. The nuclear factor-erythroid-2erelated factor 2 (Nrf2)-mediated antioxidant response pathway maintains cellular reduction-oxidation homeostasis by inducing the transcription of an array of cytoprotective genes. However, there is evidence of impaired Nrf2 response in aging contributing to age-related fibrotic diseases. Herein, we review mechanisms for the dysregulation of Nrf2 signaling in aging. This understanding will pave the way for the design of novel therapeutic strategies that restore Nrf2 signaling to reestablish cellular homeostasis in aging and age-related fibrotic diseases.

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“…DN-Nrf2, lacking the transcriptional activation domain, was generated by deleting amino acid residues 1-392 as described previously. 28 …”

Section: Nrf2 Plasmid Constructsmentioning

confidence: 99%

Flunarizine induces Nrf2-mediated transcriptional activation of heme oxygenase-1 in protection of auditory cells from cisplatin

Kim

et al. 2006

Cell Death Differ

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We investigated the cytoprotective mechanisms of flunarizine in cisplatin-induced death of auditory cells. Concomitant with an increase in viability, treatment with flunarizine resulted in a marked dissociation of Nrf2/Keap1 and subsequent intranuclear translocation of Nrf2, which was mediated by PI3K-Akt signaling. Overexpression of Nrf2 protected cells from cisplatin along with transcriptional activation of ARE to generate heme oxygenase-1 (HO-1). Pretreatment with flunarizine predominantly increased the transcriptional activity of HO-1 among Nrf2-driven transcripts, including HO-1, NQO1, GCLC, GCLM, GSTl-1, and GSTA4. Furthermore, both pharmacological inhibition and siRNA transfection of HO-1 completely abolished the flunarizine-mediated protection of HEI-OC1 cells and the primary rat (P2) organ of Corti explants from cisplatin. These results suggest that Nrf2-driven transcriptional activation of ARE through PI3K-Akt signaling augments the generation of HO-1, which may be a critically important determinant in cellular response toward cisplatin and the cytoprotective effect of flunarizine against cisplatin.

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Nrf2, a Cap'n'Collar Transcription Factor, Regulates Induction of the Heme Oxygenase-1 Gene

Cited by 1,177 publications

References 41 publications

Comparison of the Pro-Oxidative and Proinflammatory Effects of Organic Diesel Exhaust Particle Chemicals in Bronchial Epithelial Cells and Macrophages

Comparison of the Pro-Oxidative and Proinflammatory Effects of Organic Diesel Exhaust Particle Chemicals in Bronchial Epithelial Cells and Macrophages

Nuclear Factor–Erythroid-2–Related Factor 2 in Aging and Lung Fibrosis

Flunarizine induces Nrf2-mediated transcriptional activation of heme oxygenase-1 in protection of auditory cells from cisplatin

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