An Nrf2/Small Maf Heterodimer Mediates the Induction of Phase II Detoxifying Enzyme Genes through Antioxidant Response Elements

Itoh, Ken; Chiba, Tomoki; Takahashi, Satoru; Ishii, Tetsuro; Igarashi, Kazuhiko; Katoh, Yohei; Oyake, Tatsuya; Hayashi, Norio; Satoh, Keisuke; Hatayama, Ichiro; Yamamoto, Masayuki; Nabeshima, Yo‐ichi

doi:10.1006/bbrc.1997.6943

Cited by 3,538 publications

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“…Animals and experimental design C57BL/6J mice and Nrf2 -/-mice on a C57BL/6J background [9] (Riken, Japan) were housed and bred at the 'Instituto de Biologia Molecular e Celular' animal facility. Male mice (16 week-old) were fed standard rodent chow (Global rodent diet, Harlan Laboratories, Barcelona, Spain) or iron-rich diet (Global rodent diet supplemented with 2.0% carbonyl iron) for 2 weeks.…”

Section: Methodsmentioning

confidence: 99%

Transcription factor NRF2 protects mice against dietary iron-induced liver injury by preventing hepatocytic cell death

Silva‐Gomes

Santos

Caldas

et al. 2014

Journal of Hepatology

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Background & Aims:The l i v e r , being the major site of i r o n storage, is particularly exposed to the toxic effects of iron. Tran-scription factor NRF2 is critical for protecting the l i v e r a g a i n s t disease by activating the transcription of genes encoding detoxification/antioxidant enzymes. We aimed to determine if the NRF2 pathway plays a significant role in the protection against hepatic iron overload. Methods: Wild type and Nrf2 _ /_ mouse primary hepatocytes Wereincubated with ferric ammonium citrate. Wild type and Nrf2 -/-mice w e r e fed s t anda rd rodent chow or iron-rich diet for 2 weeks, with or without daily i n j e c t i o n of the a n t i o x i d a n t mito-TEMPOL. Results: In mouse hepatocytes, iron induced the nuclear translo-cation of NRF2 and the expression of cytoprotective genes in an NRF2-dependent manner. Moreover, Nrf2 _ /_ hepatocytes were highly susceptible to i r o n -induced cell d e a t h . Wild-type and Nrf2 _ /_ mice fed iron-rich diet accumulated similar amounts of iron in the liver and were equally able to increase the expression of hepatic hepcidin and ferritin. Nevertheless, in Nrf2-null mice the iron loading resulted in progressive liver injury, ranging from mild confluent necrosis to s e v e r e necroinflammatory lesio ns. Hepatocytic cell death was associated with gross ul t r a s t r u c t u r a l damage to the mitochondria. Notably, liver injury was prevented in iron-fed animals that received mito-TEMPOL. Conclusions: NRF2 protects the m o u s e liver against the t o x i c i t y of dietary iron o v e r l o a d by p r e v e n t i n g hepatocytic cell d e a t h . We identify NRF2 as a potential modifier of liver disease in iron overload pathology and show the beneficial effect of the antiox-idant mito-TEMPOL in a mouse model of dietary iron-induced liver injury. ©2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.Version: Postprint (identical content as published paper) This is a self-archived document from i3S -Instituto de Investigação e Inovação em Saúde in the University of Porto Open Repository For Open Access to more of our publications, please visit http://repositorio-aberto.up.pt/ A01/00 INTRODUCTIONIron is a component of several metalloproteins involved in crucial metabolic processes such as oxygen sensing and transport, energy metabolism and DNA synthesis. However, iron in excess is detrimental, as it can catalyze the formation of damaging radical species via Fenton-type reactions [1]. In normal conditions, iron toxicity is prevented by the binding of extracellular iron in the plasma to transferrin and by storage of intracellular iron in a protein with high storage capacity, ferritin [2]. In addition, plasma iron levels are tightly regulated by the action of the peptide hormone hepcidin. Hepcidin, which is mostly secreted in the liver, promotes the degradation of the iron exporter ferroportin expressed on the surface of iron-releasing cells, thus reducing intestinal iron absorption and its mobilization fr...

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Section: Methodsmentioning

confidence: 99%

Transcription factor NRF2 protects mice against dietary iron-induced liver injury by preventing hepatocytic cell death

Silva‐Gomes

Santos

Caldas

et al. 2014

Journal of Hepatology

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“…12 The consensus core ARE-sequence TGAC/GnnnGC binds basic leucine zipper (bZIP) transcription factors, most notably nuclear factor E2-related factor 2 (Nrf2), which forms heterodimers with other bZIP factors, such as small Maf proteins. 13,14 Under basal conditions, Nrf2 is repressed by Kelch-like ECHassociated protein 1, which facilitates proteasomal degradation of Nrf2 through Cullin-3-dependent ubiquitin ligase complex. During oxidative stress, Nrf2 escapes proteasomal degradation machinery, translocates to the nucleus and activates target gene expression via binding to ARE.…”

Section: Introductionmentioning

confidence: 99%

Oxidative stress-inducible lentiviral vectors for gene therapy

Hurttila

Kansanen

et al. 2008

Gene Ther

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Oxidative stress is important in several pathologies, including cardiovascular diseases such as atherosclerosis and cardiac ischemia-reperfusion injury. An important mechanism for adaptation to oxidative stress is induction of genes through the antioxidant response element (ARE), which regulates the expression of antioxidant and cytoprotective genes via the transcription factor Nrf2 (nuclear factor E2-related factor 2). As Nrf2-regulated genes are induced during oxidant stress occurring, for example, in reperfusion after ischemia, we took a novel approach to exploit ARE for the development of oxidative stress-inducible gene therapy vectors. To this end, one, two or three ARE-containing regions from human NAD(P)H:quinone oxidoreductase-1, glutamate-cysteine ligase modifier subunit and mouse heme oxygenase-1 were cloned into a vector expressing luciferase under a minimal SV40 promoter. The construct, which was the most responsive to ARE-inducing agents, was chosen for further studies in which a lentiviral vector was produced for an efficient transfer to endothelial cells. Heme oxygenase-1 (HO-1), which has well-characterized anti-inflammatory properties, was used as the therapeutic transgene. In human endothelial cells, AREdriven HO-1 overexpression inhibited nuclear factor-kB activation and subsequent vascular cell adhesion molecule-1 expression induced by tumor necrosis factor-a. We conclude that the ARE element is a promising alternative for the development of oxidative stress-inducible gene therapy vectors.

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“…To combat this omnipresent oxidative stress, animal cells have evolved an endogenous antioxidant response. Nuclear factor (erythroid-derived 2) (NF-E2)-related factor 2 (Nrf2), is the key regulator of antioxidant response genes, making it an essential player in this endogenous cellular antioxidant response 1,2,3,4,5,6,7 ). Nrf2 is a member of the Cap 'n' Collar family of transcription factors, which includes Nrf1, Nrf3, p45, Bach1, and Bach2 2 ).…”

Section: Introductionmentioning

confidence: 99%

“…Nrf2 binds the antioxidant responsive element (ARE), also known as the electrophile response element (EpRE)), a cis-acting regulatory element found in the 5′-flanking region of genes encoding enzymes for antioxidant production and of other Nrf2 target genes 2,3,8 ). Genes regulated by Nrf2 include heme oxygenase-1 (HO-1), ubiquitin/PKC-ζ-interacting protein A170, glutathione S-transferases (GST), NAD(P)H quinone oxidoreductase (NQO1), peroxiredoxin 1, catalasc, glutathione peroxidase, superoxide dismutase (SOD), and thioredoxin 1,4,9,10,11,12 ). Additionally, Nrf2 regulates the expression of scavenger receptors, chapcrone proteins, proteosome proteins, and transcriptional regulators 9,11 ).…”

Section: Introductionmentioning

confidence: 99%

“…Nrf2 DNA binding and transactivation both depend upon Nrf2 heterodimerazation with small Maf proteins 1,26 ). In addition to small Mafs, studies have suggested that c-Jun and activating transcription factor 4 (ATF4) also form heterodimers with Nrf2 and augment its transactivation activity 27,28 ), Further, Nrf2 has two transcriptional activation domains.…”

Section: Introductionmentioning

confidence: 99%

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Examining the Endogenous Antioxidant Response Through Immunofluorescent Analysis of Nrf2 in Tissue

Lindl

Jordan‐Sciutto

2008

Methods in Molecular Biology

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As organisms designed to depend upon oxygen to sustain life, humans are necessarily and continually exposed to damaging oxidizing agents. As a vital protective measure, oxygen-dependent organisms have developed a highly evolutionarily conserved mechanism for preventing oxidative stress. NF-E2 (nuclear factor (erythroid-derived 2))-related faetor-2 (Nrf2) is the primary regulator of this endogenous antioxidant response. Many diseases that plague human society, ranging from various cancers to neurodegenerative diseases, have oxidative stress as a component of their etiology, and thus, much disease research has focused on Nrf2, both as a potential point of biological failure and as a promising therapeutic target. As a transcription factor, Nrf2 is active only when it is nuclear, and is regulated largely by its subcellular distribution. Thus, Nrf2 protein levels and subcellular localization are both key pieces of information when studying the endogenous antioxidant response. Immunofluorescent analysis (IFA) of Nrf2 in human tissue is a particularly powerful tool in the study of Nrf2 in disease, because it allows examination of both of these regulatory mechanisms that modulate Nrf2 activity.

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An Nrf2/Small Maf Heterodimer Mediates the Induction of Phase II Detoxifying Enzyme Genes through Antioxidant Response Elements

Cited by 3,538 publications

References 46 publications

Transcription factor NRF2 protects mice against dietary iron-induced liver injury by preventing hepatocytic cell death

Transcription factor NRF2 protects mice against dietary iron-induced liver injury by preventing hepatocytic cell death

Oxidative stress-inducible lentiviral vectors for gene therapy

Examining the Endogenous Antioxidant Response Through Immunofluorescent Analysis of Nrf2 in Tissue

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