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, Yasutake; Oyake, Tatsuya; Hayashi, Norio; Satoh, Kimihiko; Hatayama, Ichiro; Yamamoto, Masayuki; Nabeshima, Yo-ichi

doi:10.1006/bbrc.1997.6943

Cited by 3,999Genomics, phytochemicals, and oxidative stressGlutathione Transferases and PolymorphismsPharmacogenetics and Drug Metabolism

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, Yasutake, Oyake, Tatsuya, Hayashi, Norio +4 more·1997·Biochemical and Biophysical Research Communications

DOI 10.1006/bbrc.1997.6943

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Abstract

The induction of phase II detoxifying enzymes is an important defense mechanism against intake of xenobiotics. While this group of enzymes is believed to be under the transcriptional control of antioxidant response elements (AREs), this contention is experimentally unconfirmed. Since the ARE resembles the binding sequence of erythroid transcription factor NF-E2, we investigated the possibility that the phase II enzyme genes might be regulated by transcription factors that also bind to the NF-E2 sequence. The expression profiles of a number of transcription factors suggest that an Nrf2/small Maf heterodimer is the most likely candidate to fulfill this role in vivo. To directly test these questions, we disrupted the murine nrf2 gene in vivo. While the expression of phase II enzymes (e.g., glutathione S-transferase and NAD(P)H: quinone oxidoreductase) was markedly induced by a phenolic antioxidant in vivo in both wild type and heterozygous mutant mice, the induction was largely eliminated in the liver and intestine of homozygous nrf2-mutant mice. Nrf2 was found to bind to the ARE with high affinity only as a heterodimer with a small Maf protein, suggesting that Nrf2/small Maf activates gene expression directly through the ARE. These results demonstrate that Nrf2 is essential for the transcriptional induction of phase II enzymes and the presence of a coordinate transcriptional regulatory mechanism for phase II enzyme genes. The nrf2-deficient mice may prove to be a very useful model for the in vivo analysis of chemical carcinogenesis and resistance to anti-cancer drugs.

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Induction of phase II enzymes through the ARE is mediated by Nrf2.
“Using in vivo studies in mice, Itoh et al. discovered that the induction of phase II enzymes through the ARE is mediated by a protein transcription factor called Nrf2 [44] (Figure 2).”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [44]
Within the nucleus, Nrf2 cannot bind to the ARE as a monomer and must heterodimerize with the small Maf protein family for transcriptional activation of antioxidant genes.
“Within the nucleus, Nrf2 cannot bind to the ARE as a monomer and must heterodimerize with the small Maf protein (sMaf) family (MafF, MafG, MafK) for transcriptional activation of antioxidant genes [44].”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [44]
Antioxidant genes regulated by Nrf2 possess functional roles to limit microglial inflammation.
“Antioxidant genes regulated by nuclear factor (erythroid-derived 2)-like 2 (Nrf2) possess functional roles to limit microglial inflammation.”
From ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020) · cites this paper as [167]
Nrf2 is a basic leucine zipper transcription factor that upregulates genes via interaction with an antioxidant response element (ARE), e.g., genes encoding NQO1 and GSTs.
“Nrf2 is a basic leucine zipper transcription factor that upregulates genes via interaction with an antioxidant response element (ARE), e.g., genes encoding NADH-quinone oxidoreductase 1 (NQO1) and glutathione-S-transferases (GSTs) [167].”
From ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020) · cites this paper as [167]

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Authors: Itoh, K., Chiba, T., Takahashi, S., Ishii, T., Igarashi, K., Katoh, Y., Oyake, T., Hayashi, N., Satoh, K., Hatayama, I., Yamamoto, M., & Nabeshima, Y.-I.
Affiliations: University of Tsukuba (JP)
Japan Science and Technology Agency (JP)
Tohoku University (JP)
Hirosaki University (JP)
National Institute of Neuroscience (JP)
Corresponding author: Yamamoto, Masayuki
ORCID: Itoh, Ken
Chiba, Tomoki
Takahashi, Satoru
Igarashi, Kazuhiko
Hayashi, Norio
Satoh, Kimihiko
Yamamoto, Masayuki
Venue: Biochemical and Biophysical Research Communications
Publisher: Elsevier BV
Published: 1997-07
Volume: 236
Issue: 2
Pages: 313-322
ISSN: 0006-291X (ISSN-L)
DOI: 10.1006/bbrc.1997.6943
OpenAlex: W1991631628
Cited by: 3,999
References: 49
Citations by year: 2026: 138 · 2025: 154 · 2024: 165 · 2023: 187 · 2022: 196 · 2021: 222 · 2020: 257 · 2019: 224 · 2018: 197 · 2017: 236 · 2016: 227 · 2015: 194 · 2014: 169 · 2013: 206 · 2012: 160
FWCI: 8.67
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: Biochemical and Biophysical Research Communications (publishedVersion)
PubMed (publishedVersion)
Funders: Japan Society for the Promotion of Science (RFTF96I00202)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Keywords: Nrf2, heterodimer, antioxidant response element, phase II enzymes, transcriptional regulation, Nrf2 knockout mice, glutathione S-transferase, NAD(P)H:quinone oxidoreductase, NF-E2, phenolic antioxidants, xenobiotic metabolism, chemical carcinogenesis, drug resistance
MeSH terms: Animals, Binding Sites, Butylated Hydroxyanisole, DNA-Binding Proteins, Glutathione Transferase, Heterozygote, Homozygote, Intestines, Liver, Male, Promoter Regions, Genetic, Quinone Reductases, Transcription Factors, Xenobiotics, Trans-Activators, Gene Expression Regulation, Enzymologic, Mice, Knockout, DNA Adducts, Dimerization, NF-E2-Related Factor 2, Mice

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

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