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Keiko Taguchi

Section

Tohoku Medical Megabank Organization

Job title

Associate Professor

Degree

Ph.D. in Medicine (University of Tsukuba)

researchmap

https://researchmap.jp/keikotaguchi

J-GLOBAL ID

200901026643356543

Research History 6

2026/04 - Present

Tohoku University　Tohoku Medical Megabank Organization　Associate Professor
2023/06 - 2026/03

Tohoku Medical Megabank Organization, Tohoku University　Visiting Associate Professor
2023/06 - 2026/03

Graduate School of Agricultural and Life Sciences, The University of Tokyo　Laboratory of Food Chemistry, Department of Applied Biological Chemistry　Associate Professor
2017/04 - 2020/03

Tohoku University　Graduate School of Medicine　Senior Assistant Professor
2008/01 - 2017/03

Tohoku University　Graduate School of Medicine　Assistant Professor
2006/04 - 2007/12

科学技術振興機構　JST-ERATO山本環境応答プロジェクト　技術員・研究員

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Committee Memberships 11

Korean Society of Toxicology　Associate Editor

2024 - Present
The Japanese Society of Toxicology　Executive board member

2022/12 - Present
The Japanese Society of Toxicology　ASIATOX

2022/07 - Present
ASIATOX Councilor　Councilor

2021/10 - Present
宮城県　環境影響評価技術審査会

2020/04 - Present
日本毒性学会　理事

2024/07 - 2026/06
第52回日本毒性学会学術年会　事務局長

2025/07 - 2025/07
第51回日本毒性学会学術年会　女性・若手企画委員会

2023/06 - 2024/07
ASIATOX-X　Scientific Committee

2023/07 - 2023/07
日本薬学会環境・衛生部会　研究戦略委員会

2016/04 - 2019/03
日本薬学会衛生薬学部会　若手研究者活性化小委員会

2013/04 - 2019/03

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Professional Memberships 5

Sociey of Toxicology

- Present
日本生化学会(2009/09-)

- Present
日本癌学会(2009/02-)

- Present
日本毒性学会（2007/01-）

- Present
日本薬学会(2004/02-)

- Present

Research Interests 3

Molecular Toxicology
衛生薬学
Biochemistry

Research Areas 3

Life sciences / Food sciences /
Life sciences / Medical biochemistry /
Life sciences / Pharmaceuticals - health and biochemistry /

Awards 11

日化協LRI賞

2025/07　一般社団法人日本化学工業協会
JB論文賞

2025　日本生化学会
東北大学医学部奨学賞（金賞）

2020/01　東北大学医学部　Keap1-Nrf2システムによる生体機能制御機構の解明
The JSOT Young Scientist Award

2017/07　The Japanese Scociety of Toxicology
41st Naito Conference Poster Award

2016/07　The Naito Foundation　Nrf2 is a critical factor for hepatocellular adenoma in impaired autophagy
Young Investigator Award

2015/12　Japanese Biochemical Society
第10回柿内三郎記念奨励研究賞

2013/09　倶進会・日本生化学会
33rd Naito Conference Poster Award

2012/06　内藤記念科学振興財団　Crosstalk between Keap1-Nrf2 system and Pten-PI3K-Akt signaling regulates cellular proliferation and differentiation
The Best Poster Award

2012/04　UK-Japan Research Symposium: Molecular Mechanisms of Stress Response in Disease　Keap1 Degradation by Autophagy for the Maintenance of Redox Homeostasis
平成22年度東北大学医学部奨学賞（銀賞）

2011/01/14　東北大学　Nrf2-Keap1生体防御システムの機能とその破綻による病態の解明
日本薬学会環境・衛生部会賞

2008/10/18　日本薬学会　酸化ストレスを生じるディーゼル排出微粒子成分の毒性発現と生体防御機構の解明

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Papers 102

Nrf2 contributes to the protective effect of iron overload on thioacetamide-induced chronic liver injury in rats. International-journal

Nanako Hamada, Yuri Ito, Hinata Niimi, Machi Atarashi, Mitsuru Kuwamura, Keiko Taguchi, Masayuki Yamamoto, Takeshi Izawa

Toxicological sciences : an official journal of the Society of Toxicology　209　(2)　2026/02/18

DOI： 10.1093/toxsci/kfaf165 　

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Chronic liver disease (CLD) is a global health concern that progresses to liver cirrhosis and cancer. This progression can be partly replicated in rodents through experimental administration of thioacetamide (TAA). Hepatic iron accumulation is a relatively common finding in CLD patients, as excess intracellular iron promotes the progression of CLD by generating reactive oxygen species. We previously reported that dietary iron overload abrogates TAA-induced liver cirrhosis in rats, raising a possibility that hepatic iron accumulation exerts a cytoprotective function. Here we investigated the role of Kelch-like ECH-associated protein 1-NF-E2-related factor 2 (Keap1-Nrf2) system in the protective effects of iron overload in TAA-induced chronic liver injury. The suppression of TAA-induced liver cirrhosis by dietary iron overload, demonstrated in wild-type rats, was cancelled in Nrf2 knockout (KO) rats, suggesting that Nrf2 contributes to the protective effect. In wild-type rats treated with both TAA and iron, major Nrf2-target gene products, NAD(P)H quinone dehydrogenase 1 and placental glutathione S-transferase (GSTP), were specifically overexpressed in hepatocytes around the fibrotic lesions. This overexpression was accompanied by iron accumulation and expression of cytochrome P450 2E1, which converts TAA into its toxic metabolites. In addition, wild-type rats treated with TAA alone developed multiple GSTP-positive preneoplastic foci, characterized by strong activation of Nrf2, partially involved by p62-dependent selective autophagy. GSTP expression was absent in hepatocytes of Nrf2 KO rats. These results suggest that Nrf2 protects liver cirrhosis and promotes formation of preneoplastic hepatocellular nodules during TAA-induced chronic liver injury depending on the hepatic iron condition.
NRF2 Activation by CDDO-Im Regulates Inflammatory and Autophagy Pathways in Human Microglial Cells International-journal

Ching-Tung Chu, Akira Uruno, Takafumi Suzuki, Keiko Taguchi, Liam Baird, Fumiki Katsuoka, Masayuki Yamamoto

Free Radical Biology and Medicine　243　318-337　2025/11
Publisher: Elsevier BV
DOI： 10.1016/j.freeradbiomed.2025.11.046 　

ISSN： 0891-5849

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Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles, accompanied by elevated oxidative stress and inflammation. Microglia, the resident macrophages in the brain, play a key protective role by clearing plaques and damaged neurons. NRF2 (Nuclear factor erythroid 2-related factor 2) is a master regulator of cytoprotection against oxidative stress, whose activation alleviates oxidative damage, neuroinflammation, and cognitive deficits in AD models. However, direct targets of NRF2 in microglia remain unclear. In this study, we demonstrate that NRF2 activation by CDDO-Im significantly suppresses inflammation in human microglial cells (HMC3) stimulated by IFN-γ or Aβ. Through integrative RNA-sequencing and ChIP-sequencing analysis of NRF2, we identified five representative direct NRF2 target genes involved in inflammation (e.g., IL6, CDK6) and another five related to autophagy (e.g., TFE3, SQSTM1). Importantly, we also found that CDDO-Im treatment enhances autophagy as evidenced by an increased LC3-II/LC3-I ratio. Public single-cell transcriptomic data further underscored the critical role of microglia in NRF2-mediated autophagy regulation within AD brains. Together, our findings reveal new direct NRF2 target genes, highlight the dual role of NRF2 in suppressing inflammation and enhancing autophagy, and thus provide novel insights for therapeutic interventions in AD.
NRF2の人工呼吸関連肺傷害(VILI)におけるbiotrauma抑制効果の検討

武井祐介, 田口恵子, 鈴木隆史, 山田充啓, 齋藤和智, 江島豊, 山内正憲, 山本雅之

日本集中治療医学会雑誌　32　(Suppl.2)　S564-S564　2025/09
Publisher: (一社)日本集中治療医学会
ISSN： 1340-7988

eISSN： 1882-966X
Cisplatin-induced genetic alterations in KEAP1 promote therapeutic resistance in head and neck squamous cell carcinoma. International-journal

Yuki Nakayama, Keiko Taguchi, Shun Wakamori, Akira Uruno, Akihito Otsuki, Akira Ohkoshi, Hidekazu Shirota, Tomoyuki Iwasaki, Yukio Katori, Masayuki Yamamoto

Redox biology　86　103819-103819　2025/08/11

DOI： 10.1016/j.redox.2025.103819 　

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Cisplatin (CDDP) resistance remains a major challenge in the treatment of recurrent head and neck squamous cell carcinoma (HNSCC). The KEAP1-NRF2 system, a central regulator of cellular redox homeostasis, is frequently altered in cancer, but its contribution to acquired CDDP resistance in HNSCC remains to be clarified. To address this, we investigated NRF2 activation in CDDP resistance using seven parental (P) HNSCC cell lines and their CDDP-resistant (CR) derivatives. Among these P-CR pairs, three CR lines exhibited elevated NRF2 expression; two harbored KEAP1 mutations, and one had an NFE2L2 mutation that were present in both P and CR lines. These NRF2-high CR lines showed upregulation of NRF2 target genes and enrichment of xenobiotic metabolism and reactive oxygen species pathways. Mitomycin C (MMC), a cytotoxic agent for its synthetic lethality in NRF2-activated cancer cells, demonstrated strong cytotoxicity specifically in these NRF2-high CR lines. Immunohistochemical analysis on clinical samples found that high NRF2 expression was significantly associated with poor prognosis and was frequently observed in recurrent tumors following chemoradiotherapy with CDDP. These results suggest that CDDP therapy, while initially effective, may paradoxically promote tumor progression and therapeutic resistance by aberrantly activating the KEAP1-NRF2 axis. This redox-driven adaptation highlights a critical characteristic in NRF2-hyperactivated HNSCC that is exploitable by MMC treatment.
Gender differences in plasma element concentrations and associations between selenoprotein P and iron metabolism in a community-based cohort study. International-journal

Yoshiro Saito, Misaki Shimizu, Mitsuharu Sato, An Masuda, Kotoko Arisawa, Keiko Taguchi, Takashi Toyama, Ikuko N Motoike, Kengo Kinoshita, Seizo Koshiba, Masayuki Yamamoto, Toshinari Takamura

Scientific reports　15　(1)　25319-25319　2025/07/13

DOI： 10.1038/s41598-025-10581-2 　

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Essential trace elements, such as iron (Fe) and selenium (Se), play physiological roles in our body, whereas environmental toxic metals, such as arsenic (As), cadmium (Cd), and mercury (Hg), are known to be associated with various disease risks. However, the relationship between elements, biochemical parameters, and lifestyle habits based on multi-elemental analysis in healthy individuals has not been fully verified. Multi-elemental analysis is useful for evaluating the change in the concentration of these elements and metals. In the present study using totally 100 µL plasma samples from the Tohoku Medical Megabank (TMM) community-based cohort study (total of 506 specimens), we conducted a multi-elemental analysis to evaluate 14 elements in generally healthy subjects. We further determined Se-transporter selenoprotein P levels using the originally developed ELISA method, since increases and decreases in selenoprotein P levels are associated with various disease risks. Multiple correlation analyses between the obtained measured values and several factors suggest that elements such as Fe, Se, and Hg, as well as selenoprotein P levels, are associated with gender differences. We also found that factors such as Fe, Se, As, Hg, hematocrit value, hemoglobin (Hb) content, and HbA1c are correlated with selenoprotein P levels. Furthermore, correlations between Fe levels and Hb content and between As/Hg and fish consumption were found. These findings demonstrate the suitability of multi-elemental analyses with limited plasma sample amounts, clearly show gender-differentiated elements, and establish a significant relationship between selenoprotein P and Fe metabolism.
Diverse Cre recombinase expression pattern in Albumin-Cre driver rats.

Saeko Ishida, Keiko Taguchi, Ryuya Iida, Kosuke Hattori, Hiroaki Taketsuru, Kazuto Yoshimi, Masayuki Yamamoto, Tomoji Mashimo

Experimental animals　74　(3)　328-334　2025/07/11

DOI： 10.1538/expanim.24-0174 　

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Rats (Rattus norvegicus) have been widely utilized as model animals due to their physiological characteristics, making them suitable for surgical and long-term studies. They have played a crucial role in biomedical research, complementing studies conducted in mice. The advent of genome editing technologies has facilitated the generation of genetically modified rat strains, advancing studies in experimental animals. Among these innovations, Cre-driver rat models have emerged as powerful tools for spatiotemporal control of gene expression. However, their development and characterization remain less advanced compared to mouse models. In this study, we developed liver-targeting Cre knock-in rats and reporter knock-in rats to evaluate Cre recombinase expression profiles in different genetic contexts. Our results revealed that insertion orientation and promoter origin significantly influence Cre expression patterns. Notably, forward insertion of the Albumin (Alb) promoter-driven Cre sequence at the ROSA26 locus resulted in ubiquitous Cre expression, while reverse insertion confined Cre expression predominantly to the liver. Interestingly, Cre expression under an endogenous Alb promoter unexpectedly induced expression in non-liver tissues, which may suggest a potential link to the in vivo dynamics of albumin. These findings underscore the importance of rigorous characterization in Cre-based transgenic systems. By elucidating the roles of promoter origin, insertion site, and orientation, our study provides valuable insights for optimizing Cre-driver rat models. These findings pave the way for refining genetic strategies to enhance tissue specificity and reliability in functional genomics and disease modeling.
Health position paper and redox perspectives - Bench to bedside transition for pharmacological regulation of NRF2 in noncommunicable diseases. International-journal

Antonio Cuadrado, Eduardo Cazalla, Anders Bach, Boushra Bathish, Sharadha Dayalan Naidu, Gina M DeNicola, Albena T Dinkova-Kostova, Raquel Fernández-Ginés, Anna Grochot-Przeczek, John D Hayes, Thomas W Kensler, Rafael León, Karen T Liby, Manuela G López, Gina Manda, Akshatha Kalavathi Shivakumar, Henriikka Hakomäki, Jessica A Moerland, Hozumi Motohashi, Ana I Rojo, Gerasimos P Sykiotis, Keiko Taguchi, Ángela M Valverde, Masayuki Yamamoto, Anna-Liisa Levonen

Redox biology　81　103569-103569　2025/04

DOI： 10.1016/j.redox.2025.103569 　

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Nuclear factor erythroid 2-related factor 2 (NRF2) is a redox-activated transcription factor regulating cellular defense against oxidative stress, thereby playing a pivotal role in maintaining cellular homeostasis. Its dysregulation is implicated in the progression of a wide array of human diseases, making NRF2 a compelling target for therapeutic interventions. However, challenges persist in drug discovery and safe targeting of NRF2, as unresolved questions remain especially regarding its context-specific role in diseases and off-target effects. This comprehensive review discusses the dualistic role of NRF2 in disease pathophysiology, covering its protective and/or destructive roles in autoimmune, respiratory, cardiovascular, and metabolic diseases, as well as diseases of the digestive system and cancer. Additionally, we also review the development of drugs that either activate or inhibit NRF2, discuss main barriers in translating NRF2-based therapies from bench to bedside, and consider the ways to monitor NRF2 activation in vivo.
Anticancer Effect of C19-Position Substituted Geldanamycin Derivatives Targeting NRF2-NQO1-activated Esophageal Squamous Cell Carcinoma International-journal

Hiroyuki Oshikiri, Keiko Taguchi, Wataru Hirose, Yusuke Taniyama, Takashi Kamei, David Siegel, David Ross, Russell R. A. Kitson, Liam Baird, Masayuki Yamamoto

Molecular and Cellular Biology　45　(2)　79-97　2025/02

DOI： 10.1080/10985549.2024.2438817 　

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In esophageal squamous cell carcinoma, genetic activation of NRF2 increases resistance to chemotherapy and radiotherapy, which results in a significantly worse prognosis for patients. Therefore NRF2-activated cancers create an urgent clinical need to identify new therapeutic options. In this context, we previously identified the geldanamycin family of HSP90 inhibitors, which includes 17DMAG, to be synthetic lethal with NRF2 activity. As the first-generation of geldanamycin-derivative drugs were withdrawn from clinical trials due to hepatotoxicity, we designed second-generation compounds with C19-substituted structures in order to inhibit glutathione conjugation-mediated hepatotoxicity. In this study, using a variety of in vitro and in vivo cancer models, we found that C19-substituted 17DMAG compounds maintain their enhanced toxicity profile and synthetic lethal interaction with NRF2-NQO1-activated cancer cells. Importantly, using a xenograft mouse tumor model, we found that C19-substituted 17DMAG displayed significant anticancer efficacy against NRF2-NQO1-activated cancer cells without causing hepatotoxicity. These results clearly demonstrate the improved clinical potential for this new class of HSP90 inhibitor anticancer drugs, and suggest that patients with NRF2-NQO1-activated esophageal carcinoma may benefit from this novel therapeutic approach.
Bag1 protein loss sensitizes mouse embryonic fibroblasts to glutathione depletion. International-journal

Atsushi Inose-Maruyama, Hayato Irokawa, Kouki Takeda, Keiko Taguchi, Masanobu Morita, Masayuki Yamamoto, Masato Sasaki, Shusuke Kuge

Cell stress & chaperones　29　(3)　497-509　2024/06

DOI： 10.1016/j.cstres.2024.05.003 　

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Bcl2-associated athanogene-1 protein (Bag1) acts as a co-chaperone of heat shock protein 70 and heat shock cognate 70 and regulates multiple cellular processes, including cell proliferation, apoptosis, environmental stress response, and drug resistance. Since Bag1 knockout mice exhibited fetal lethality, the in vivo function of Bag1 remains unclear. In this study, we established a mouse line expressing Bag1 gene missing exon 5, which corresponds to an encoding region for the interface of heat shock protein 70/heat shock cognate 70. Despite mice carrying homoalleles of the Bag1 mutant (Bag1Δex5) expressing undetectable levels of Bag1, Bag1Δex5 homozygous mice developed without abnormalities. Bag1Δex5 protein was found to be highly unstable in cells and in vitro. We found that the growth of mouse embryonic fibroblasts derived from Bag1Δex5-homo mice was attenuated by doxorubicin and a glutathione (GSH) synthesis inhibitor, buthionine sulfoximine. In response to buthionine sulfoximine, Bag1Δex5-mouse embryonic fibroblasts exhibited a higher dropping rate of GSH relative to the oxidized glutathione level. In addition, Bag1 might mitigate cellular hydrogen peroxide levels. Taken together, our results demonstrate that the loss of Bag1 did not affect mouse development and that Bag1 is involved in intracellular GSH homeostasis, namely redox homeostasis.
Whole blood transcriptome analysis for age- and gender-specific gene expression profiling in Japanese individuals. International-journal Peer-reviewed

Yu-Ichi Aoki, Keiko Taguchi, Hayato Anzawa, Junko Kawashima, Noriko Ishida, Akihito Otuki, Atsushi Hasegawa, Liam Baird, Takafumi Suzuki, Ikuko N Motoike, Kinuko Ohneda, Kazuki Kumada, Fumiki Katsuoka, Kengo Kinoshita, Masayuki Yamamoto

Journal of biochemistry　175　(6)　611-627　2024/01/24

DOI： 10.1093/jb/mvae008 　

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Whole blood transcriptome analysis is a valuable approach in medical research, primarily due to the ease of sample collection and the richness of the information obtained. Since the expression profile of individual genes in the analysis is influenced by medical traits and demographic attributes such as age and gender, there has been a growing demand for a comprehensive database for blood transcriptome analysis. Here, we performed whole blood RNA sequencing (RNA-seq) analysis on 576 participants stratified by age (20-30s and 60-70s) and gender from cohorts of the Tohoku Medical Megabank (TMM). A part of female segment included pregnant women. We did not exclude the globin gene family in our RNA-seq study, which enabled us to identify instances of hereditary persistence of fetal hemoglobin based on the HBG1 and HBG2 expression information. Comparing stratified populations allowed us to identify groups of genes associated with age-related changes and gender differences. We also found that the immune response status, particularly measured by neutrophil-to-lymphocyte ratio (NLR), strongly influences the diversity of individual gene expression profiles in whole blood transcriptome analysis. This stratification has resulted in a dataset that will be highly beneficial for future whole blood transcriptome analysis in the Japanese population.
Sulforaphane decreases serum selenoprotein P levels through enhancement of lysosomal degradation independent of Nrf2 International-journal Peer-reviewed

Xinying Ye, Takashi Toyama, Keiko Taguchi, Kotoko Arisawa, Takayuki Kaneko, Ryouhei Tsutsumi, Masayuki Yamamoto, Yoshiro Saito

Communications Biology　6　(1)　1060-1060　2023/10/19
Publisher: Springer Science and Business Media LLC
DOI： 10.1038/s42003-023-05449-y 　

eISSN： 2399-3642

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Abstract Selenoprotein P (SeP) is a major selenoprotein in serum predominantly produced in the liver. Excess SeP impairs insulin secretion from the pancreas and insulin sensitivity in skeletal muscle, thus inhibition of SeP could be a therapeutic strategy for type 2 diabetes. In this study, we examine the effect of sulforaphane (SFN), a phytochemical of broccoli sprouts and an Nrf2 activator, on SeP expression in vitro and in vivo. Treatment of HepG2 cells with SFN decreases inter- and intra-cellular SeP levels. SFN enhances lysosomal acidification and expression of V-ATPase, and inhibition of this process cancels the decrease of SeP by SFN. SFN activates Nrf2 in the cells, while Nrf2 siRNA does not affect the decrease of SeP by SFN or lysosomal acidification. These results indicate that SFN decreases SeP by enhancing lysosomal degradation, independent of Nrf2. Injection of SFN to mice results in induction of cathepsin and a decrease of SeP in serum. The findings from this study are expected to contribute to developing SeP inhibitors in the future, thereby contributing to treating and preventing diseases related to increased SeP.
A NRF2-induced secretory phenotype activates immune surveillance to remove irreparably damaged cells International-journal Peer-reviewed

Liam Baird, Keiko Taguchi, Anqi Zhang, Yushi Takahashi, Takafumi Suzuki, Thomas W. Kensler, Masayuki Yamamoto

Redox Biology　66　102845-102845　2023/10
Publisher: Elsevier BV
DOI： 10.1016/j.redox.2023.102845 　

ISSN： 2213-2317

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While it is well established that the KEAP1-NRF2 pathway regulates the main inducible cellular response to oxidative stress, this cytoprotective function of NRF2 could become deleterious to the host if it confers survival onto irreparably damaged cells. In this regard, we have found that in diseased states, NRF2 promotes the transcriptional activation of a specific subset of the senescence-associated secretory phenotype (SASP) gene program, which we have named the NRF2-induced secretory phenotype (NISP). In two models of hepatic disease using Pten::Keap1 and Keap1::Atg7 double knockout mice, we found that the NISP functions in the liver to recruit CCR2 expressing monocytes, which function as immune system effector cells to directly remove the damaged cells. Through activation of this immune surveillance pathway, in non-transformed cells, NRF2 functions as a tumour suppressor to mitigate the long-term survival of damaged cells which otherwise would be detrimental for host survival. This pathway represents the final stage of the oxidative stress response, as it allows cells to be safely removed if the macromolecular damage caused by the original stressor is so extensive that it is beyond the repair capacity of the cell.
Metabolic reprogramming in Nrf2-driven proliferation of normal rat hepatocytes. International-journal Peer-reviewed

Marta Anna Kowalik, Keiko Taguchi, Marina Serra, Andrea Caddeo, Elisabetta Puliga, Marina Bacci, Seizo Koshiba, Jin Inoue, Eiji Hishinuma, Andrea Morandi, Silvia Giordano, Andrea Perra, Masayuki Yamamoto, Amedeo Columbano

Hepatology (Baltimore, Md.)　79　(4)　829-843　2023/08/21

DOI： 10.1097/HEP.0000000000000568 　

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BACKGROUND AIMS: Cancer cells reprogram their metabolic pathways to support bioenergetic and biosynthetic needs and to maintain their redox balance. In several human tumors the Keap1-Nrf2 system controls proliferation and metabolic reprogramming by regulating the pentose phosphate pathway (PPP). However, whether this metabolic reprogramming also occurs in normal proliferating cells is unclear. APPROACH AND RESULTS: To define the metabolic phenotype in normal proliferating hepatocytes, we induced cell proliferation in the liver by three distinct stimuli: liver regeneration by partial hepatectomy (PH) and hepatic hyperplasia induced by two direct mitogens, lead nitrate (LN) or triiodothyronine (T3). Following LN treatment, well-established features of cancer metabolic reprogramming including enhanced glycolysis, oxidative PPP, nucleic acid synthesis, NAD+/NADH synthesis and altered amino acid content as well as downregulated oxidative phosphorylation (OXPHOS) occurred in normal proliferating hepatocytes displaying Nrf2 activation. Genetic deletion of Nrf2 blunted LN-induced PPP activation and suppressed hepatocyte proliferation. Moreover, Nrf2 activation and following metabolic reprogramming did not occur when hepatocyte proliferation was induced by PH or T3. CONCLUSION: Many metabolic changes in cancer cells are shared by proliferating normal hepatocytes in response to a hostile environment. Nrf2 activation is essential for bridging metabolic changes with crucial components of cancer metabolic reprogramming including the activation of oxidative PPP. Our study demonstrates that matured hepatocytes exposed to LN undergo a cancer-like metabolic reprogramming and offers a rapid and useful in vivo model to study the molecular alterations underpinning the differences/similarities of metabolic changes in normal and neoplastic hepatocytes.
Nrf2 alleviates spaceflight-induced immunosuppression and thrombotic microangiopathy in mice International-journal Peer-reviewed

Shimizu R, Hirano I, Hasegawa A, Suzuki M, Otsuki A, Taguchi K, Katsuoka F, Uruno A, Suzuki N, Yumoto A, Okada R, Shrakawa M, Shiba D, Takahashi S, Suzuki T, Yamamoto M

Commun Biol　6　(1)　875-875　2023/08

DOI： 10.1038/s42003-022-03316-w 　

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Spaceflight-related stresses impact health via various body systems, including the haematopoietic and immune systems, with effects ranging from moderate alterations of homoeostasis to serious illness. Oxidative stress appears to be involved in these changes, and the transcription factor Nrf2, which regulates expression of a set of cytoprotective and antioxidative stress response genes, has been implicated in the response to spaceflight-induced stresses. Here, we show through analyses of mice from the MHU-3 project, in which Nrf2-knockout mice travelled in space for 31 days, that mice lacking Nrf2 suffer more seriously from spaceflight-induced immunosuppression than wild-type mice. We discovered that a one-month spaceflight-triggered the expression of tissue inflammatory marker genes in wild-type mice, an effect that was even more pronounced in the absence of Nrf2. Concomitant with induction of inflammatory conditions, the consumption of coagulation-fibrinolytic factors and platelets was elevated by spaceflight and further accelerated by Nrf2 deficiency. These results highlight that Nrf2 mitigates spaceflight-induced inflammation, subsequent immunosuppression, and thrombotic microangiopathy. These observations reveal a new strategy to relieve health problems encountered during spaceflight.
jMorp: Japanese Multi Omics Reference Panel

田高周, 菱沼英史, 井上仁, 青木裕一, 岡村容伸, 川嶋順子, 大槻晃史, 田口恵子, 菅野貴成, 元池育子, 勝岡史城, 小柴生造, 木下賢吾

トーゴーの日2022　1　2022/10/05
Publisher: JST NBDC事業推進部
DOI： 10.18908/togo2022.p040 　
The KEAP1-NRF2 System and Esophageal Cancer. International-journal Peer-reviewed

Wataru Hirose, Hiroyuki Oshikiri, Keiko Taguchi, Masayuki Yamamoto

Cancers　14　(19)　2022/09/27

DOI： 10.3390/cancers14194702 　

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NRF2 (nuclear factor erythroid 2-related factor 2) is a transcription factor that regulates the expression of many cytoprotective genes. NRF2 activation is mainly regulated by KEAP1 (kelch-like ECH-associated protein 1) through ubiquitination and proteasome degradation. Esophageal cancer is classified histologically into two major types: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). ESCC harbors more genetic alterations in the KEAP-NRF2 system than EAC does, which results in NRF2 activation in these cancers. NRF2-addicted ESCC exhibits increased malignancy and acquisition of resistance to chemoradiotherapy. Therefore, it has been recognized that the development of drugs targeting the KEAP1-NRF2 system based on the molecular dissection of NRF2 function is important and urgent for the treatment of ESCC, along with efficient clinical screening for NRF2-addicted ESCC patients. Recently, the fate of NRF2-activated cells in esophageal tissues, which was under the influence of strong cell competition, and its relationship to the pathogenesis of ESCC, was clarified. In this review, we will summarize the current knowledge of the KEAP1-NRF2 system and the treatment of ESCC. We propose three main strategies for the treatment of NRF2-addicted cancer: (1) NRF2 inhibitors, (2) synthetic lethal drugs for NRF2-addicted cancers, and (3) NRF2 inducers of the host defense system.
Construction of a trio-based structural variation panel utilizing activated T lymphocytes and long-read sequencing technology. International-journal Peer-reviewed

Akihito Otsuki, Yasunobu Okamura, Noriko Ishida, Shu Tadaka, Jun Takayama, Kazuki Kumada, Junko Kawashima, Keiko Taguchi, Naoko Minegishi, Shinichi Kuriyama, Gen Tamiya, Kengo Kinoshita, Fumiki Katsuoka, Masayuki Yamamoto

Communications biology　5　(1)　991-991　2022/09/20

DOI： 10.1038/s42003-022-03953-1 　

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Long-read sequencing technology enable better characterization of structural variants (SVs). To adapt the technology to population-scale analyses, one critical issue is to obtain sufficient amount of high-molecular-weight genomic DNA. Here, we propose utilizing activated T lymphocytes, which can be established efficiently in a biobank to stably supply high-grade genomic DNA sufficiently. We conducted nanopore sequencing of 333 individuals constituting 111 trios with high-coverage long-read sequencing data (depth 22.2x, N50 of 25.8 kb) and identified 74,201 SVs. Our trio-based analysis revealed that more than 95% of the SVs were concordant with Mendelian inheritance. We also identified SVs associated with clinical phenotypes, all of which appear to be stably transmitted from parents to offspring. Our data provide a catalog of SVs in the general Japanese population, and the applied approach using the activated T-lymphocyte resource will contribute to biobank-based human genetic studies focusing on SVs at the population scale.
Selective Elimination of NRF2-Activated Cells by Competition with Neighboring Cells in the Esophageal Epithelium. International-journal Peer-reviewed

Wataru Hirose, Makoto Horiuchi, Donghan Li, Ikuko N Motoike, Lin Zhang, Hafumi Nishi, Yusuke Taniyama, Takashi Kamei, Mikiko Suzuki, Kengo Kinoshita, Fumiki Katsuoka, Keiko Taguchi, Masayuki Yamamoto

Cellular and molecular gastroenterology and hepatology　15　(1)　153-178　2022/09/14

DOI： 10.1016/j.jcmgh.2022.09.004 　

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BACKGROUND & AIMS: NF-E2-related factor 2 (NRF2) is a transcription factor that regulates cytoprotective gene expression in response to oxidative and electrophilic stresses. NRF2 activity is mainly controlled by Kelch-like ECH-associated protein 1 (KEAP1). Constitutive NRF2 activation by NRF2 mutations or KEAP1 dysfunction results in a poor prognosis for esophageal squamous cell carcinoma (ESCC) through the activation of cytoprotective functions. However, the detailed contributions of NRF2 to ESCC initiation or promotion have not been clarified. Here, we investigated the fate of NRF2-activated cells in the esophageal epithelium. METHODS: We generated tamoxifen-inducible, squamous epithelium-specific Keap1 conditional knockout (Keap1-cKO) mice in which NRF2 was inducibly activated in a subset of cells at the adult stage. Histological, quantitative reverse-transcription polymerase chain reaction (qRT‒PCR), single-cell RNA-sequencing (RNA-seq) and carcinogen experiments were conducted to analyze the Keap1-cKO esophagus. RESULTS: KEAP1-deleted/NRF2-activated cells and cells with normal NRF2 expression (KEAP1-normal cells) coexisted in the Keap1-cKO esophageal epithelium in approximately equal numbers, and NRF2-activated cells formed dysplastic lesions. NRF2-activated cells exhibited weaker attachment to the basement membrane and gradually disappeared from the epithelium. In contrast, neighboring KEAP1-normal cells exhibited accelerated proliferation and started dominating the epithelium but accumulated DNA damage that triggered carcinogenesis upon carcinogen exposure. CONCLUSIONS: Constitutive NRF2 activation promotes the selective elimination of epithelial cells via cell competition, but this competition induces DNA damage in neighboring KEAP1-normal cells, which predisposes them to chemical-induced ESCC.
Redox Homeostasis is Disturbed by Redox Cycling between Reactive Cysteines of Thioredoxin 1 and 9,10-Phenanthrenequinone, an Atmospheric Electron Acceptor. International-journal Peer-reviewed

Yumi Abiko, Keiko Taguchi, Miwa Hisamori, Kyoko Hiyoshi-Arai, Nho Cong Luong, Akira Toriba, Yoshito Kumagai

Chemical research in toxicology　35　(8)　1425-1432　2022/08/15

DOI： 10.1021/acs.chemrestox.2c00174 　

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9,10-Phenanthrenequinone (9,10-PQ) is a toxicant in diesel exhaust particles and airborne particulate matter ≤2.5 μm in diameter. It is an efficient electron acceptor that readily reacts with dithiol compounds in vitro, resulting in the oxidation of thiol groups and concomitant generation of reactive oxygen species (ROS). However, it remains to be elucidated whether 9,10-PQ interacts with proximal protein dithiols. In the present study, we used thioredoxin 1 (Trx1) as a model of proteins with reactive proximal cysteines and examined whether it reacts with 9,10-PQ in cells and tissues, thereby affecting its catalytic activity and thiol status. Intratracheal injection of 9,10-PQ into mice resulted in protein oxidation and diminished Trx activity in the lungs. Using recombinant wild-type and C32S/C35S Trx1, we found that Cys32 and Cys35 selectively serve as electron donor sites for redox reactions with 9,10-PQ that lead to substantial inhibition of Trx activity. Addition of dithiothreitol restored the Trx activity inhibited by 9,10-PQ. Exposure of cultured cells to 9,10-PQ caused intracellular reactive oxygen species generation that led to protein oxidation, Trx1 dimerization, p38 phosphorylation, and apoptotic cell death. Overexpression of Trx1 blocked these 9,10-PQ-mediated events. These results suggest that the interaction of the reactive cysteines of Trx1 with 9,10-PQ causes oxidative stress, leading to disruption of redox homeostasis.
Nrf2 protects against radiation-induced oral mucositis via antioxidation and keratin layer thickening. International-journal Peer-reviewed

Shun Wakamori, Keiko Taguchi, Yuki Nakayama, Akira Ohkoshi, Michael B Sporn, Takenori Ogawa, Yukio Katori, Masayuki Yamamoto

Free radical biology & medicine　188　206-220　2022/08/01

DOI： 10.1016/j.freeradbiomed.2022.06.239 　

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Radiation-induced oral mucositis is one of the most common adverse events in radiation therapy for head and neck cancers, but treatments for oral mucositis are limited to palliative and supportive care. New approaches are required to prevent radiation-induced mucositis and to improve treatments. The Keap1-Nrf2 system regulates cytoprotection against oxidative and electrophilic stresses. Nrf2 also regulates keratin layer thickness in mouse tongues. Therefore, we hypothesized that Nrf2 may protect the tongue epithelium against radiation-induced mucositis via elimination of reactive oxygen species and induction of keratin layer thickening. To test this hypothesis, we prepared a system for γ-ray exposure of restricted areas and irradiated the tongues of model mice with Nrf2 and Keap1 loss-of-function. We discovered that loss of Nrf2 expression indeed sensitized the tongue epithelium to radiation-induced ulcer formation with inflammation. Constitutive Nrf2 activation by genetic Keap1 knockdown alleviated radiation-induced DNA damage by increasing antioxidation. In agreement with the genetic Nrf2 activation model, the Nrf2 inducer CDDO-Im prevented irradiation damage to the tongue epithelium. These results demonstrate that Nrf2 activation has the potential to prevent the development of radiation-induced mucositis and that Nrf2 inducers are an important therapeutic drug for protection of the upper aerodigestive tract from radiation-induced mucositis.
The β-TrCP-Mediated Pathway Cooperates with the Keap1-Mediated Pathway in Nrf2 Degradation In Vivo. International-journal

Ayumi Kuga, Kouhei Tsuchida, Harit Panda, Makoto Horiuchi, Akihito Otsuki, Keiko Taguchi, Fumiki Katsuoka, Mikiko Suzuki, Masayuki Yamamoto

Molecular and cellular biology　42　(7)　e0056321　2022/07/21

DOI： 10.1128/mcb.00563-21 　

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Nrf2 activates cytoprotective gene expression, and Nrf2 activity is regulated through at least two protein degradation pathways: the Keap1-mediated and β-TrCP-mediated pathways. To address the relative contributions of these pathways, we generated knock-in mouse lines expressing an Nrf2SA mutant that harbored two substitution mutations of serine residues interacting with β-TrCP. The homozygous (Nrf2SA/SA) mice grew normally, with Nrf2 levels comparable to those of wild-type (WT) mice under unstressed conditions. However, when Keap1 activity was suppressed, high levels of Nrf2 accumulated in Nrf2SA/SA macrophages compared with that in WT macrophages. We crossed Nrf2SA/SA mice with mice in which Keap1 was knocked down to two different levels. We found that the Nrf2SA/SA mutation induced higher Nrf2 activity when the Keap1 level was strongly reduced, and these mice showed severe growth retardation. However, activation and growth retardation were not evident when Keap1 was moderately suppressed. These increases in Nrf2 activity induced by the Nrf2SA mutation caused severe hyperplasia and hyperkeratosis in the esophageal epithelium but did not cause abnormalities in the other tissues/organs examined. These results indicate that the β-TrCP-mediated pathway cooperates with the Keap1-mediated pathway to regulate Nrf2 activity, which is apparent when the Keap1-mediated pathway is profoundly suppressed.
AHR and NRF2 in Skin Homeostasis and Atopic Dermatitis. International-journal

Tomohiro Edamitsu, Keiko Taguchi, Ryuhei Okuyama, Masayuki Yamamoto

Antioxidants (Basel, Switzerland)　11　(2)　2022/01/25

DOI： 10.3390/antiox11020227 　

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Skin is constantly exposed to environmental insults, including toxic chemicals and oxidative stress. These insults often provoke perturbation of epidermal homeostasis and lead to characteristic skin diseases. AHR (aryl hydrocarbon receptor) and NRF2 (nuclear factor erythroid 2-related factor 2) are transcription factors that induce a battery of cytoprotective genes encoding detoxication and antioxidant enzymes in response to environmental insults. In addition to their basic functions as key regulators of xenobiotic and oxidant detoxification, recent investigations revealed that AHR and NRF2 also play critical roles in the maintenance of skin homeostasis. In fact, specific disruption of AHR function in the skin has been found to be associated with the pathogenesis of various skin diseases, most prevalently atopic dermatitis (AD). In this review, current knowledge on the roles that AHR and NRF2 play in epidermal homeostasis was summarized. Functional annotations of genetic variants, both regulatory and nonsynonymous SNPs, identified in the AHR and NRF2 loci in the human genome were also summarized. Finally, the possibility that AHR and NRF2 serve as therapeutic targets of AD was assessed.
Nrf2 plays a critical role in the metabolic response during and after spaceflight International-journal

Akira Uruno, Daisuke Saigusa, Takafumi Suzuki, Akane Yumoto, Tomohiro Nakamura, Naomi Matsukawa, Takahiro Yamazaki, Ristumi Saito, Keiko Taguchi, Mikiko Suzuki, Norio Suzuki, Akihito Otsuki, Fumiki Katsuoka, Eiji Hishinuma, Risa Okada, Seizo Koshiba, Yoshihisa Tomioka, Ritsuko Shimizu, Masaki Shirakawa, Thomas W. Kensler, Dai Shiba, Masayuki Yamamoto

Communications Biology　4　(1)　1381-1381　2021/12
Publisher: Springer Science and Business Media LLC
DOI： 10.1038/s42003-021-02904-6 　

eISSN： 2399-3642

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<title>Abstract</title>Space travel induces stresses that contribute to health problems, as well as inducing the expression of Nrf2 (NF-E2-related factor-2) target genes that mediate adaptive responses to oxidative and other stress responses. The volume of epididymal white adipose tissue (eWAT) in mice increases during spaceflight, a change that is attenuated by <italic>Nrf2</italic> knockout. We conducted metabolome analyses of plasma from wild-type and <italic>Nrf2</italic> knockout mice collected at pre-flight, in-flight and post-flight time points, as well as tissues collected post-flight to clarify the metabolic responses during and after spaceflight and the contribution of Nrf2 to these responses. Plasma glycerophospholipid and sphingolipid levels were elevated during spaceflight, whereas triacylglycerol levels were lower after spaceflight. In wild-type mouse eWAT, triacylglycerol levels were increased, but phosphatidylcholine levels were decreased, and these changes were attenuated in <italic>Nrf2</italic> knockout mice. Transcriptome analyses revealed marked changes in the expression of lipid-related genes in the liver and eWAT after spaceflight and the effects of <italic>Nrf2</italic> knockout on these changes. Based on these results, we concluded that space stress provokes significant responses in lipid metabolism during and after spaceflight; Nrf2 plays critical roles in these responses.
Gene expression changes related to bone mineralization, blood pressure and lipid metabolism in mouse kidneys after space travel International-journal

Norio Suzuki, Yuma Iwamura, Taku Nakai, Koichiro Kato, Akihito Otsuki, Akira Uruno, Daisuke Saigusa, Keiko Taguchi, Mikiko Suzuki, Ritsuko Shimizu, Akane Yumoto, Risa Okada, Masaki Shirakawa, Dai Shiba, Satoru Takahashi, Takafumi Suzuki, Masayuki Yamamoto

Kidney International　101　(1)　92-105　2021/11
Publisher: Elsevier BV
DOI： 10.1016/j.kint.2021.09.031 　

ISSN： 0085-2538

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Space travel burdens health by imposing considerable environmental stress associated with radioactivity and microgravity. In particular, gravity change predominantly impacts blood pressure and bone homeostasis, both of which are controlled mainly by the kidneys. Nuclear factor erythroid-2-related transcription factor 2 (Nrf2) plays essential roles in protecting the kidneys from various environmental stresses and injuries. To elucidate the effects of space travel on mammals in preparation for the upcoming space era, our study investigated the contribution of Nrf2 to kidney function in mice two days after their return from a 31-day stay in the International Space Station using Nrf2 knockout mice. Meaningfully, expression levels of genes regulating bone mineralization, blood pressure and lipid metabolism were found to be significantly altered in the kidneys after space travel in an Nrf2-independent manner. In particular, uridine diphosphate-glucuronosyltransferase 1A (Ugt1a) isoform genes were found to be expressed in an Nrf2-dependent manner and induced exclusively in the kidneys after return to Earth. Since spaceflight elevated the concentrations of fatty acids in the mouse plasma, we suggest that Ugt1a isoform expression in the kidneys was induced to promote glucuronidation of excessively accumulated lipids and excrete them into urine after the return from space. Thus, the kidneys were proven to play central roles in adaptation to gravity changes caused by going to and returning from space by controlling blood pressure and bone mineralization. Additionally, kidney Ugt1a isoform induction after space travel implies a significant role of the kidneys for space travelers in the excretion of excessive lipids.
Nuclear Factor Erythroid 2-Related Factor 2 Depletion Sensitizes Pancreatic Cancer Cells to Gemcitabine via Aldehyde Dehydrogenase 3a1 Repression. International-journal

Ryotaro Matsumoto, Shin Hamada, Yu Tanaka, Keiko Taguchi, Masayuki Yamamoto, Atsushi Masamune

The Journal of pharmacology and experimental therapeutics　379　(1)　33-40　2021/10

DOI： 10.1124/jpet.121.000744 　

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As the central regulator of the oxidative stress response, nuclear factor erythroid 2-related factor 2 (Nrf2) is attracting great interest as a therapeutic target for various cancers, and the possible clinical applications of novel Nrf2 inhibitors have been explored in Nrf2-activated cancers. In the present study, we specifically investigated halofuginone, which is derived from a natural plant alkaloid. We found that halofuginone administration decreased the number of pancreatic intraepithelial neoplasias in pancreas-specific Kras and p53 mutant (KPC) mice. In Nrf2-activated pancreatic cancer cell lines established from KPC mice, halofuginone rapidly depleted Nrf2 in Nrf2-activated cancer cells. Both in vitro and in vivo, it sensitized Nrf2-activated pancreatic cancer cells to gemcitabine, which is the first-line chemotherapy in clinical practice. In our mechanistic study, we found that halofuginone downregulated aldehyde dehydrogenase 3a1 (ALDH3A1) in mouse pancreatic cancer cells. The Nrf2 inducer diethyl maleate upregulated ALDH3A1, and knockdown of Aldh3a1 sensitized Nrf2-activated cancer cells to gemcitabine, strongly suggesting that ALDH3A1 is regulated by Nrf2 and that it contributes to gemcitabine resistance. The current study demonstrated the therapeutic benefits of halofuginone in Nrf2-activated pancreatic cancers. SIGNIFICANCE STATEMENT: We identified nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream target aldehyde dehydrogenase 3a1 (ALDH3A1) as novel therapeutic targets in pancreatic cancer. They negatively affect the efficacy of a conventional chemotherapeutic agent, gemcitabine. We confirmed that Nrf2 plays a pivotal role in the induction of ALDH3A1.
Nrf2 expression in pancreatic stellate cells promotes progression of cancer. International-journal

Yu Tanaka, Shin Hamada, Ryotaro Matsumoto, Keiko Taguchi, Masayuki Yamamoto, Atsushi Masamune

American journal of physiology. Gastrointestinal and liver physiology　321　(4)　G378-G388　2021/10/01

DOI： 10.1152/ajpgi.00120.2021 　

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It was previously identified that systemic Nrf2 deletion attenuates pancreatic cancer progression in a mutant K-ras/p53-expressing mouse model (KPC mouse). In this study, the type of cell that is responsible for the retarded cancer progression was elucidated. Human pancreatic cancers were first examined, and elevated expression of NRF2-target gene products in α-smooth muscle actin-positive cells was found, suggesting that pancreatic stellate cells (PSCs) are involved in this process. Closer examination of primary cultured PSCs from Nrf2-deleted mice revealed that the cells were less proliferative and retained a lower migration capacity. The conditioned medium of Nrf2-deleted PSCs exhibited reduced growth-stimulating effects in pancreatic cancer cells. KPC mouse-derived pancreatic cancer cells coinjected with wild-type PSCs developed significantly larger subcutaneous tumors in immunodeficient mice than those coinjected with Nrf2-deleted PSCs. These results demonstrate that Nrf2 actively contributes to the function of PSCs to sustain KPC cancer progression, thus, suggesting that Nrf2 inhibition in PSCs may be therapeutically important in pancreatic cancer.NEW & NOTEWORTHY This study identified that Nrf2 contributes to PSC activation. Nrf2 deletion in PSCs resulted in attenuation of cancer-promoting role. Nrf2 in PSCs could be an attractive therapeutic target in pancreatic cancer.
転写因子Nrf2の活性化が引き起こす食道異形成と発がんにおける細胞選択性

堀内真, 谷山裕亮, 田口恵子, 鈴木未来子, 山本雅之, 亀井尚

日本外科学会定期学術集会抄録集　121回　PS-5　2021/04
Publisher: (一社)日本外科学会
Nrf2 Activation Sensitizes K-Ras Mutant Pancreatic Cancer Cells to Glutaminase Inhibition. International-journal Peer-reviewed

Shin Hamada, Ryotaro Matsumoto, Yu Tanaka, Keiko Taguchi, Masayuki Yamamoto, Atsushi Masamune

International journal of molecular sciences　22　(4)　2021/02/14

DOI： 10.3390/ijms22041870 　

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Pancreatic cancer remains intractable owing to the lack of effective therapy for unresectable cases. Activating mutations of K-ras are frequently found in pancreatic cancers, but these have not yet been targeted by cancer therapies. The Keap1-Nrf2 system plays a crucial role in mediating the oxidative stress response, which also contributes to cancer progression. Nrf2 activation reprograms the metabolic profile to promote the proliferation of cancer cells. A recent report suggested that K-ras- and Nrf2-active lung cancer cells are sensitive to glutamine depletion. This finding led to the recognition of glutaminase inhibitors as novel anticancer agents. In the current study, we used murine pancreatic cancer tissues driven by mutant K-ras and p53 to establish cell lines expressing constitutively activated Nrf2. Genetic or pharmacological Nrf2 activation in cells via Keap1 deletion or Nrf2 activation sensitized cells to glutaminase inhibition. This phenomenon was confirmed to be dependent on K-ras activation in human pancreatic cancer cell lines harboring mutant K-ras, i.e., Panc-1 and MiaPaCa-2 in response to DEM pretreatment. This phenomenon was not observed in BxPC3 cells harboring wildtype K-ras. These results indicate the possibility of employing Nrf2 activation and glutaminase inhibition as novel therapeutic interventions for K-ras mutant pancreatic cancers.
Cellular Nrf2 Levels Determine Cell Fate during Chemical Carcinogenesis in Esophageal Epithelium. International-journal Peer-reviewed

Makoto Horiuchi, Keiko Taguchi, Wataru Hirose, Kouhei Tsuchida, Mikiko Suzuki, Yusuke Taniyama, Takashi Kamei, Masayuki Yamamoto

Molecular and cellular biology　41　(2)　2021/01/25

DOI： 10.1128/MCB.00536-20 　

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Nrf2 is essential for cytoprotection against carcinogens, and through systemic Nrf2 knockout mice, Nrf2-deficient cells were shown to be susceptible to chemical carcinogens and prone to developing cancers. However, the oncogenic potential of Nrf2-deficient epithelial cells surrounded by normal cells in the esophagus could not be assessed by previous models, and the fate of Nrf2-deficient cells in such situations remains elusive. In this study, therefore, we generated mice that harbor almost equal levels of cells with Nrf2 deleted and those with Nrf2 intact in the basal layer of the esophageal epithelium, utilizing inducible Cre-mediated recombination of Nrf2 alleles in adults through moderate use of tamoxifen. In this mouse model, epithelial cells with Nrf2 deleted were maintained with no obvious decrease or phenotypic changes for 12 weeks under unstressed conditions. Upon exposure to the carcinogen 4-nitroquinoline-1-oxide (4NQO), the cells with Nrf2 deleted accumulated DNA damage and selectively disappeared from the epithelium, so almost all 4NQO-induced tumors originated from cells with Nrf2 intact and not from those with Nrf2 deleted. We propose that cells with Nrf2 deleted do not undergo carcinogenesis due to selective elimination upon exposure to 4NQO, indicating that cellular Nrf2 abundance and the epithelial environment determine the cell fate or oncogenic potential of esophageal epithelial cells in 4NQO-induced carcinogenesis.
The KEAP1-NRF2 System as a Molecular Target of Cancer Treatment. International-journal Peer-reviewed

Keiko Taguchi, Masayuki Yamamoto

Cancers　13　(1)　2020/12/26

DOI： 10.3390/cancers13010046 　

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The Kelch-like ECH-associated protein (KEAP1)- Nuclear factor erythroid-derived 2-like 2 (encoded by the Nfe2l2 gene; NRF2) system attracts extensive interest from scientists in basic and clinical cancer research fields, as NRF2 exhibits activity as both an oncogene and tumor suppressor, depending on the context. Especially unique and malignant, NRF2-addicted cancers exhibit high levels of NRF2 expression. Somatic mutations identified in the NRF2 or KEAP1 genes of NRF2-addicted cancers cause the stabilization and accumulation of NRF2. NRF2-addicted cancers hijack the intrinsic roles that NRF2 plays in cytoprotection, including antioxidative and anti-electrophilic responses, as well as metabolic reprogramming, and acquire a marked advantage to survive under severe and limited microenvironments. Therefore, NRF2 inhibitors are expected to have therapeutic effects in patients with NRF2-addicted cancers. In contrast, NRF2 activation in host immune cells exerts significant suppression of cancer cell growth, indicating that NRF2 inducers also have the potential to be therapeutics for cancers. Thus, the KEAP1-NRF2 system makes a broad range of contributions to both cancer development and suppression. These observations thus demonstrate that both NRF2 inhibitors and inducers are useful for the treatment of cancers with high NRF2 activity.
転写因子Nrf2の活性化が引き起こす食道異形成と発がんにおける細胞選択性

堀内真, 田口恵子, 鈴木未来子, 谷山裕亮, 山本雅之, 亀井尚

日本食道学会学術集会プログラム・抄録集　74回　110-110　2020/12
Publisher: (NPO)日本食道学会
Author Correction: Nrf2 contributes to the weight gain of mice during space travel. International-journal

Takafumi Suzuki, Akira Uruno, Akane Yumoto, Keiko Taguchi, Mikiko Suzuki, Nobuhiko Harada, Rie Ryoke, Eriko Naganuma, Nanae Osanai, Aya Goto, Hiromi Suda, Ryan Browne, Akihito Otsuki, Fumiki Katsuoka, Michael Zorzi, Takahiro Yamazaki, Daisuke Saigusa, Seizo Koshiba, Takashi Nakamura, Satoshi Fukumoto, Hironobu Ikehata, Keizo Nishikawa, Norio Suzuki, Ikuo Hirano, Ritsuko Shimizu, Tetsuya Oishi, Hozumi Motohashi, Hirona Tsubouchi, Risa Okada, Takashi Kudo, Michihiko Shimomura, Thomas W Kensler, Hiroyasu Mizuno, Masaki Shirakawa, Satoru Takahashi, Dai Shiba, Masayuki Yamamoto

Communications biology　3　(1)　566-566　2020/10/07

DOI： 10.1038/s42003-020-01292-7 　

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An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Nrf2 contributes to the weight gain of mice during space travel. International-journal Peer-reviewed

Takafumi Suzuki, Akira Uruno, Akane Yumoto, Keiko Taguchi, Mikiko Suzuki, Nobuhiko Harada, Rie Ryoke, Eriko Naganuma, Nanae Osanai, Aya Goto, Hiromi Suda, Ryan Browne, Akihito Otsuki, Fumiki Katsuoka, Michael Zorzi, Takahiro Yamazaki, Daisuke Saigusa, Seizo Koshiba, Takashi Nakamura, Satoshi Fukumoto, Hironobu Ikehata, Keizo Nishikawa, Norio Suzuki, Ikuo Hirano, Ritsuko Shimizu, Tetsuya Oishi, Hozumi Motohashi, Hirona Tsubouchi, Risa Okada, Takashi Kudo, Michihiko Shimomura, Thomas W Kensler, Hiroyasu Mizuno, Masaki Shirakawa, Satoru Takahashi, Dai Shiba, Masayuki Yamamoto

Communications biology　3　(1)　496-496　2020/09/08

DOI： 10.1038/s42003-020-01227-2 　

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Space flight produces an extreme environment with unique stressors, but little is known about how our body responds to these stresses. While there are many intractable limitations for in-flight space research, some can be overcome by utilizing gene knockout-disease model mice. Here, we report how deletion of Nrf2, a master regulator of stress defense pathways, affects the health of mice transported for a stay in the International Space Station (ISS). After 31 days in the ISS, all flight mice returned safely to Earth. Transcriptome and metabolome analyses revealed that the stresses of space travel evoked ageing-like changes of plasma metabolites and activated the Nrf2 signaling pathway. Especially, Nrf2 was found to be important for maintaining homeostasis of white adipose tissues. This study opens approaches for future space research utilizing murine gene knockout-disease models, and provides insights into mitigating space-induced stresses that limit the further exploration of space by humans.
Nrf2 in liver toxicology. International-journal Peer-reviewed

Keiko Taguchi, Thomas W Kensler

Archives of pharmacal research　43　(3)　337-349　2020/03

DOI： 10.1007/s12272-019-01192-3 　

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Liver plays essential roles in the metabolism of many endogenous chemicals and exogenous toxicants. Mechanistic studies in liver have been at the forefront of efforts to probe the roles of bioactivation and detoxication of environmental toxins and toxicants in hepatotoxicity. Moreover, idiosyncratic hepatoxicity remains a key barrier in the clinical development of drugs. The now vast Nrf2 field emerged in part from biochemical and molecular studies on chemical inducers of hepatic detoxication enzymes and subsequent characterization of the modulation of drug/toxicant induced hepatotoxicities in mice through disruption of either Nrf2 or Keap1 genes. In general, loss of Nrf2 increases the sensitivity to such toxic chemicals, highlighting a central role of this transcription factor and its downstream target genes as a modifier to chemical stress. In this review, we summarize the impact of Nrf2 on the toxicology of multiple hepatotoxicants, and discuss efforts to utilize the Nrf2 response in predictive toxicology.
Keap1 deletion accelerates mutant K-ras/p53-driven cholangiocarcinoma. International-journal Peer-reviewed

Tatsuhide Nabeshima, Shin Hamada, Keiko Taguchi, Yu Tanaka, Ryotaro Matsumoto, Masayuki Yamamoto, Atsushi Masamune

American journal of physiology. Gastrointestinal and liver physiology　318　(3)　G419-G427　2020/03/01

DOI： 10.1152/ajpgi.00296.2019 　

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The activation of the Kelch-like ECH-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) pathway contributes to cancer progression in addition to oxidative stress responses. Loss-of-function Keap1 mutations were reported to activate Nrf2, leading to cancer progression. We examined the effects of Keap1 deletion in a cholangiocarcinoma mouse model using a mutant K-ras/p53 mouse. Introduction of the Keap1 deletion into liver-specific mutant K-ras/p53 expression resulted in the formation of invasive cholangiocarcinoma. Comprehensive analyses of the gene expression profiles identified broad upregulation of Nrf2-target genes such as Nqo1 and Gstm1 in the Keap1-deleted mutant K-ras/p53 expressing livers, accompanied by upregulation of cholangiocyte-related genes. Among these genes, the transcriptional factor Sox9 was highly expressed in the dysplastic bile duct. The Keap-Nrf2-Sox9 axis might serve as a novel therapeutic target for cholangiocarcinoma.NEW & NOTEWORTHY The Keap1-Nrf2 system has a wide variety of effects in addition to the oxidative stress response in cancer cells. Addition of the liver-specific Keap1 deletion to mice harboring mutant K-ras and p53 accelerated cholangiocarcinoma formation, together with the hallmarks of Nrf2 activation. This process involved the expansion of Sox9-positive cells, indicating increased differentiation toward the cholangiocyte phenotype.
Aryl Hydrocarbon Receptor Directly Regulates Artemin Gene Expression. International-journal Peer-reviewed

Tomohiro Edamitsu, Keiko Taguchi, Eri H Kobayashi, Ryuhei Okuyama, Masayuki Yamamoto

Molecular and cellular biology　39　(20)　2019/10/15

DOI： 10.1128/MCB.00190-19 　

ISSN： 0270-7306

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Transgenic mice expressing a constitutively active form of the aryl hydrocarbon receptor in keratinocytes (AhR-CA mice) develop severe dermatitis that substantially recapitulates the pathology of human atopic dermatitis. The neurotrophic factor artemin (Artn) is highly expressed in the epidermis of AhR-CA mice and causes hypersensitivity to itch (alloknesis) by elongating nerves into the epidermis. However, whether the Artn gene is regulated directly by AhR or indirectly through complex regulation associated with AhR remains unclear. To this end, we previously conducted chromatin immunoprecipitation-sequencing analyses of the Artn locus and found a xenobiotic response element (XRE) motif located far upstream (52 kb) of the gene. Therefore, in this study, we addressed whether the XRE actually regulates the Artn gene expression by deleting the region containing the motif. We generated two lines of ArtnΔXRE mice. In the mouse epidermis, inducible expression of the Artn gene by the AhR agonist 3-methylcholanthrene was substantially suppressed compared to that in wild-type mice. Importantly, in AhR-CA::ArtnΔXRE mice, Artn expression was significantly suppressed, and alloknesis was improved. These results demonstrate that the Artn gene is indeed regulated by the distal XRE-containing enhancer, and alloknesis in AhR-CA mice is provoked by the AhR-mediated direct induction of the Artn gene.
Keap1欠失ラットはNrf2に依存して重篤な肝障害を引き起こす

田口恵子, 小山内七重, 佐藤由莉, 真下知士, 山本雅之

The Journal of Toxicological Sciences　44　(Suppl.)　S225-S225　2019/06
Publisher: (一社)日本毒性学会
ISSN： 0388-1350

eISSN： 1880-3989
Nrf2 Activation Ameliorates Hepatotoxicity Induced by a Heme Synthesis Inhibitor. International-journal Peer-reviewed

Keiko Taguchi, Saho Masui, Tohru Itoh, Atsushi Miyajima, Masayuki Yamamoto

Toxicological sciences : an official journal of the Society of Toxicology　167　(1)　227-238　2019/01/01

DOI： 10.1093/toxsci/kfy233 　

ISSN： 1096-6080

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Transcription factor Nrf2 protects hepatocytes against various toxicants by upregulating cytoprotective genes. The heme synthesis inhibitor 3, 5-diethoxycarbonyl-1, 4-dihydrocollidine (DDC) leads to liver injury around the portal vein, unlike other groups of toxicants that cause hemorrhage and necrosis in the centrilobular area. To examine whether and how Nrf2 protects livers from the injury, we fed DDC to Nrf2 knockout (Nrf2KO), wild-type (WT), Keap1flox/flox (Keap1-knockdown; Keap1KD), and liver-specific Keap1 knockout (Keap1-Alb) mice, as these lines of mice exhibit stepwise increases in Nrf2 protein expression levels. Liver-specific Keap1::Nrf2 double-knockout (Keap1::Nrf2-Alb) mice were also exploited to examine the contribution of Nrf2. Two weeks after DDC feeding, Keap1-Alb mice were fully recovered from body weight loss, but the WT and Nrf2KO mice were not. The liver-to-body-weight ratio of Keap1-Alb mice was significantly larger than that of WT and Nrf2KO mice. Two indicators of hepatotoxicity, alanine aminotransferase and bilirubin in plasma, were both elevated in WT mice, but downregulated in Keap1-Alb mice after the DDC-feeding. DDC-induced porphyrin accumulation was reduced in the livers of Keap1-Alb and Keap1KD mice compared with that of WT mice. When assessed by the Nqo1 level, Nrf2 expression was further enhanced by DDC in Keap1-Alb mice, suggesting that DDC may have a Keap1 independent potential to activate Nrf2. Genetic activation of Nrf2 in Keap1-Alb mice increased the extracellular excretion of porphyrins, but contrary to our expectation, hepatic damages in Nrf2KO mice appeared to be similar to that of WT mice. Based on these observations, we conclude that Nrf2 activation protects livers against DDC-elicited hepatotoxicity.
Genetic inactivation of Nrf2 prevents clonal expansion of initiated cells in a nutritional model of rat hepatocarcinogenesis. International-journal Peer-reviewed

Claudia Orrù, Marta Szydlowska, Keiko Taguchi, Patrizia Zavattari, Andrea Perra, Masayuki Yamamoto, Amedeo Columbano

Journal of hepatology　69　(3)　635-643　2018/09
Publisher: Elsevier B.V.
DOI： 10.1016/j.jhep.2018.05.010 　

ISSN： 1600-0641 0168-8278
Hyperactivation of Nrf2 leads to hypoplasia of bone in vivo. International-journal Peer-reviewed

Eiki Yoshida, Takafumi Suzuki, Masanobu Morita, Keiko Taguchi, Kohei Tsuchida, Hozumi Motohashi, Minoru Doita, Masayuki Yamamoto

Genes to cells : devoted to molecular & cellular mechanisms　23　(5)　386-392　2018/05
Publisher: Blackwell Publishing Ltd
DOI： 10.1111/gtc.12579 　

ISSN： 1365-2443 1356-9597
Simultaneous K-ras activation and Keap1 deletion cause atrophy of pancreatic parenchyma. International-journal Peer-reviewed

Shin Hamada, Tooru Shimosegawa, Keiko Taguchi, Tatsuhide Nabeshima, Masayuki Yamamoto, Atsushi Masamune

American journal of physiology. Gastrointestinal and liver physiology　314　(1)　G65-G74-G74　2018/01/01
Publisher: American Physiological Society
DOI： 10.1152/ajpgi.00228.2017 　

ISSN： 1522-1547 0193-1857
Discovery of novel aminobenzisoxazole derivatives as orally available factor IXa inhibitors. International-journal

Isao Sakurada, Toshiya Endo, Katsuyoshi Hikita, Tomokazu Hirabayashi, Yoshitaka Hosaka, Yutaka Kato, Yoshitaka Maeda, Shigeki Matsumoto, Takashi Mizuno, Hiroshi Nagasue, Teruyuki Nishimura, Shunsuke Shimada, Mikihiko Shinozaki, Keiko Taguchi, Katsutoshi Takeuchi, Tooru Yokoyama, Alan Hruza, Paul Reichert, Ting Zhang, Harold B Wood, Kazunari Nakao, Shoji Furusako

Bioorganic & medicinal chemistry letters　27　(11)　2622-2628　2017/06/01

DOI： 10.1016/j.bmcl.2017.03.002 　

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Using structure based drug design, novel aminobenzisoxazoles as coagulation factor IXa inhibitors were designed and synthesized. Highly selective inhibition of FIXa over FXa was demonstrated. Anticoagulation profile of selected compounds was evaluated by aPTT and PT tests. In vitro ADMET and pharmacokinetic (PK) profiles were also evaluated.
Nrf2 promotes mutant K-ras/p53-driven pancreatic carcinogenesis. International-journal Peer-reviewed

Shin Hamada, Keiko Taguchi, Atsushi Masamune, Masayuki Yamamoto, Tooru Shimosegawa

Carcinogenesis　38　(6)　661-670　2017/06/01

DOI： 10.1093/carcin/bgx043 　

ISSN： 0143-3334

eISSN： 1460-2180
The KEAP1-NRF2 System in Cancer. International-journal Peer-reviewed

Keiko Taguchi, Masayuki Yamamoto

Frontiers in oncology　7　(MAY)　85-85　2017
Publisher: Frontiers Media S.A.
DOI： 10.3389/fonc.2017.00085 　

ISSN： 2234-943X
[Integrated regulation of Nrf2 by two protein degradation systems]. Invited

Keiko Taguchi

Seikagaku. The Journal of Japanese Biochemical Society　88　(5)　630-8　2016/10
Publisher: Japanese Biochemical Society
DOI： 10.14952/SEIKAGAKU.2016.880630 　

ISSN： 0037-1017
Generation of a New Model Rat: Nrf2 Knockout Rats Are Sensitive to Aflatoxin B1 Toxicity. International-journal Peer-reviewed

Keiko Taguchi, Misaki Takaku, Patricia A Egner, Masanobu Morita, Takehito Kaneko, Tomoji Mashimo, Thomas W Kensler, Masayuki Yamamoto

Toxicological sciences : an official journal of the Society of Toxicology　152　(1)　40-52　2016/07

DOI： 10.1093/toxsci/kfw065 　

ISSN： 1096-6080

eISSN： 1096-0929
p62/Sqstm1 promotes malignancy of HCV-positive hepatocellular carcinoma through Nrf2-dependent metabolic reprogramming. International-journal Peer-reviewed

Tetsuya Saito, Yoshinobu Ichimura, Keiko Taguchi, Takafumi Suzuki, Tsunehiro Mizushima, Kenji Takagi, Yuki Hirose, Masayuki Nagahashi, Tetsuro Iso, Toshiaki Fukutomi, Maki Ohishi, Keiko Endo, Takefumi Uemura, Yasumasa Nishito, Shujiro Okuda, Miki Obata, Tsuguka Kouno, Riyo Imamura, Yukio Tada, Rika Obata, Daisuke Yasuda, Kyoko Takahashi, Tsutomu Fujimura, Jingbo Pi, Myung-Shik Lee, Takashi Ueno, Tomoyuki Ohe, Tadahiko Mashino, Toshifumi Wakai, Hirotatsu Kojima, Takayoshi Okabe, Tetsuo Nagano, Hozumi Motohashi, Satoshi Waguri, Tomoyoshi Soga, Masayuki Yamamoto, Keiji Tanaka, Masaaki Komatsu

Nature communications　7　12030-12030　2016/06/27

DOI： 10.1038/ncomms12030 　

ISSN： 2041-1723
Partial contribution of the Keap1-Nrf2 system to cadmium-mediated metallothionein expression in vascular endothelial cells. International-journal Peer-reviewed

Yasuhiro Shinkai, Tomoki Kimura, Ayaka Itagaki, Chika Yamamoto, Keiko Taguchi, Masayuki Yamamoto, Yoshito Kumagai, Toshiyuki Kaji

Toxicology and applied pharmacology　295　37-46　2016/03/15

DOI： 10.1016/j.taap.2016.01.020 　

ISSN： 0041-008X

eISSN： 1096-0333
Constitutive Nrf2 activation ameliorates hepatotoxicity induced by a heme synthesis Inhibitor

TAGUCHI Keiko, MASUI Saho, YAMAMOTO Masayuki

Annual Meeting of the Japanese Society of Toxicology　43　(Supplement)　O-46　2016
Publisher: The Japanese Society of Toxicology
DOI： 10.14869/toxpt.43.1.0_O-46 　

ISSN： 0388-1350
The Transcription Factor Bach2 Is Phosphorylated at Multiple Sites in Murine B Cells but a Single Site Prevents Its Nuclear Localization International-journal Peer-reviewed

Ryo Ando, Hiroki Shima, Toru Tamahara, Yoshihiro Sato, Miki Watanabe-Matsui, Hiroki Kato, Nicolas Sax, Hozumi Motohashi, Keiko Taguchi, Masayuki Yamamoto, Masaki Nio, Tatsuya Maeda, Kyoko Ochiai, Akihiko Muto, Kazuhiko Igarashi

JOURNAL OF BIOLOGICAL CHEMISTRY　291　(4)　1826-1840　2016/01

DOI： 10.1074/jbc.M115.661702 　

ISSN： 0021-9258

eISSN： 1083-351X
Keap1-Nrf2 regulatory system and cancer Peer-reviewed

Keiko Taguchi, Masayuki Yamamoto

Protein Modifications in Pathogenic Dysregulation of Signaling　269-285　2015/09/02
Publisher: Springer Japan
DOI： 10.1007/978-4-431-55561-2_17 　
Activation of the NRF2 pathway and its impact on the prognosis of anaplastic glioma patients. International-journal Peer-reviewed

Masayuki Kanamori, Tsuyoshi Higa, Yukihiko Sonoda, Shohei Murakami, Mina Dodo, Hiroshi Kitamura, Keiko Taguchi, Tatsuhiro Shibata, Mika Watanabe, Hiroyoshi Suzuki, Ichiyo Shibahara, Ryuta Saito, Yoji Yamashita, Toshihiro Kumabe, Masayuki Yamamoto, Hozumi Motohashi, Teiji Tominaga

Neuro-oncology　17　(4)　555-65　2015/04

DOI： 10.1093/neuonc/nou282 　

ISSN： 1522-8517

eISSN： 1523-5866
Nrf2 knockout rats are sensitive to hepatic toxicity by Aflatoxin B₁

TAGUCHI Keiko, TAKAKU Misaki, KENSLER Thomas W., YAMAMOTO Masayuki

Annual Meeting of the Japanese Society of Toxicology　42　(Supplement)　O-12　2015
Publisher: The Japanese Society of Toxicology
DOI： 10.14869/toxpt.42.1.0_O-12 　

ISSN： 0388-1350
NF-E2-related factor 2 promotes compensatory liver hypertrophy after portal vein branch ligation in mice. International-journal Peer-reviewed

Keiichi Shirasaki, Keiko Taguchi, Michiaki Unno, Hozumi Motohashi, Masayuki Yamamoto

Hepatology (Baltimore, Md.)　59　(6)　2371-82　2014/06

DOI： 10.1002/hep.27020 　

ISSN： 0270-9139

eISSN： 1527-3350
Keap1 inhibition attenuates glomerulosclerosis. International-journal Peer-reviewed

Yoichi Miyazaki, Akihiro Shimizu, Ira Pastan, Keiko Taguchi, Eriko Naganuma, Takafumi Suzuki, Tatsuo Hosoya, Takashi Yokoo, Akihiko Saito, Toshio Miyata, Masayuki Yamamoto, Taiji Matsusaka

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association　29　(4)　783-91　2014/04

DOI： 10.1093/ndt/gfu002 　

ISSN： 0931-0509

eISSN： 1460-2385
The circadian clock regulates rhythmic activation of the NRF2/glutathione-mediated antioxidant defense pathway to modulate pulmonary fibrosis. International-journal Peer-reviewed

Vanja Pekovic-Vaughan, Julie Gibbs, Hikari Yoshitane, Nan Yang, Dharshika Pathiranage, Baoqiang Guo, Aya Sagami, Keiko Taguchi, David Bechtold, Andrew Loudon, Masayuki Yamamoto, Jefferson Chan, Gijsbertus T J van der Horst, Yoshitaka Fukada, Qing-Jun Meng

Genes & development　28　(6)　548-60　2014/03/15

DOI： 10.1101/gad.237081.113 　

ISSN： 0890-9369

eISSN： 1549-5477
Nrf2 enhances cholangiocyte expansion in Pten-deficient livers. International-journal Peer-reviewed

Keiko Taguchi, Ikuo Hirano, Tohru Itoh, Minoru Tanaka, Atsushi Miyajima, Akira Suzuki, Hozumi Motohashi, Masayuki Yamamoto

Molecular and cellular biology　34　(5)　900-13　2014/03

DOI： 10.1128/MCB.01384-13 　

ISSN： 0270-7306

eISSN： 1098-5549
Critical role of Nrf2 in oxidative stress-induced retinal ganglion cell death. International-journal Peer-reviewed

Noriko Himori, Kotaro Yamamoto, Kazuichi Maruyama, Morin Ryu, Keiko Taguchi, Masayuki Yamamoto, Toru Nakazawa

Journal of neurochemistry　127　(5)　669-80　2013/12

DOI： 10.1111/jnc.12325 　

ISSN： 0022-3042

eISSN： 1471-4159
肝毒性物質による肝肥大におけるNrf2の貢献

田口恵子, 本橋ほづみ, 伊藤暢, 田中稔, 宮島篤, 山本雅之

日本生化学会大会プログラム・講演要旨集　86回　2P-246　2013/09
Publisher: (公社)日本生化学会
The role of the Nrf2-mediated defense system in corneal epithelial wound healing. International-journal Peer-reviewed

Ryuhei Hayashi, Noriko Himori, Keiko Taguchi, Yuki Ishikawa, Kohji Uesugi, Miyuki Ito, Thomas Duncan, Motokazu Tsujikawa, Toru Nakazawa, Masayuki Yamamoto, Kohji Nishida

Free radical biology & medicine　61　333-42　2013/08

DOI： 10.1016/j.freeradbiomed.2013.04.008 　

ISSN： 0891-5849 1873-4596
Interaction of 9,10-phenanthraquinone with dithiol causes oxidative modification of Cu,Zn-superoxide dismutase (SOD) through redox cycling Peer-reviewed

Rie Koizumi, Keiko Taguchi, Miwa Hisamori, Yoshito Kumagai

Journal of Toxicological Sciences　38　(3)　317-324　2013/06

DOI： 10.2131/jts.38.317 　

ISSN： 1880-3989 0388-1350

eISSN： 1880-3989
Metabolic stress response implicated in diabetic retinopathy: the role of calpain, and the therapeutic impact of calpain inhibitor. International-journal Peer-reviewed

Ahmed Y Shanab, Toru Nakazawa, Morin Ryu, Yuji Tanaka, Noriko Himori, Keiko Taguchi, Masayuki Yasuda, Ryo Watanabe, Jiro Takano, Takaomi Saido, Naoko Minegishi, Toshio Miyata, Toshiaki Abe, Masayuki Yamamoto

Neurobiology of disease　48　(3)　556-67　2012/12

DOI： 10.1016/j.nbd.2012.07.025 　

ISSN： 0969-9961
Keap1 degradation by autophagy for the maintenance of redox homeostasis. International-journal Peer-reviewed

Keiko Taguchi, Nanako Fujikawa, Masaaki Komatsu, Tetsuro Ishii, Michiaki Unno, Takaaki Akaike, Hozumi Motohashi, Masayuki Yamamoto

Proceedings of the National Academy of Sciences of the United States of America　109　(34)　13561-6　2012/08/21

DOI： 10.1073/pnas.1121572109 　

ISSN： 0027-8424
Nrf2 inhibits hepatic iron accumulation and counteracts oxidative stress-induced liver injury in nutritional steatohepatitis. Peer-reviewed

Kosuke Okada, Eiji Warabi, Hirokazu Sugimoto, Masaki Horie, Katsutoshi Tokushige, Tetsuya Ueda, Nobuhiko Harada, Keiko Taguchi, Etsuko Hashimoto, Ken Itoh, Tetsuro Ishii, Hirotoshi Utsunomiya, Masayuki Yamamoto, Junichi Shoda

Journal of gastroenterology　47　(8)　924-35　2012/08

DOI： 10.1007/s00535-012-0552-9 　

ISSN： 0944-1174
Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. International-journal Peer-reviewed

Yoichiro Mitsuishi, Keiko Taguchi, Yukie Kawatani, Tatsuhiro Shibata, Toshihiro Nukiwa, Hiroyuki Aburatani, Masayuki Yamamoto, Hozumi Motohashi

Cancer cell　22　(1)　66-79　2012/07/10

DOI： 10.1016/j.ccr.2012.05.016 　

ISSN： 1535-6108
Molecular basis of Keap1-Nrf2 system function

YAMAMOTO Masayuki, TAGUCHI Keiko, SUZUKI Takafumi, MOTOHASHI Hozumi

Annual Meeting of the Japanese Society of Toxicology　39　SL3　2012
Publisher: The Japanese Society of Toxicology
DOI： 10.14869/toxpt.39.2.0.SL3.0 　

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Our bodies must counteract insults originating from the environment. Toxic chemicals (electrophiles) and reactive oxygen species (ROS) activate expression of detoxifying and antioxidant genes through antioxidant responsive element (ARE). Transcription factor Nrf2 is essential for the coordinated induction of cellular defense enzymes through ARE. This notion is best demonstrated in animal models, showing that Nrf2-null mice are sensitive to a wide variety of electrophiles and ROS. Keap1 is identified as a negative regulator of Nrf2. Electrophiles liberate Nrf2 from the repression by Keap1 and provoke nuclear accumulation of Nrf2. Keap1 possesses multiple reactive cysteine residues that covalently bound with electrophiles, indicating that Keap1 acts as a sensor for xenobiotic stresses and we refer this system to as the Cysteine Code. Mouse and zebrafish models demonstrate that multiple sensor functions reside within Keap1. The hinge and latch model proposed for the Keap1-Nrf2 system describes the regulation of nuclear accumulation of Nrf2 by a Cul3- Keap1 E3 ubiquitin ligase-dependent mechanism. We have verified this model through structure biology, mouse/zebrafish genetics and human cancer analyses. In human cancers, missense mutations have been identified in KEAP1 and NRF2 genes. These mutations disrupt the KEAP1-NRF2 complex and result in constitutive activation of NRF2. Elevated expression of NRF2 target genes confers advantages on cancer cells. Transgenic mouse models provide evidence that mutated form of Keap1 analogous to cancer genotypes lose the ability to repress Nrf2 in vivo. Thus, the Keap1-Nrf2 system opens a new avenue to the understanding of the signal transduction and regulatory processes underlying the stress response and cancer progression.
Keap1-Nrf2 system for maintenance of redox homeostasis

TAGUCHI Keiko, FUJIKAWA Nanako, MOTOHASHI Hozumi, YAMAMOTO Masayuki

Annual Meeting of the Japanese Society of Toxicology　39　AS3-4　2012
Publisher: The Japanese Society of Toxicology
DOI： 10.14869/toxpt.39.2.0.AS3-4.0 　

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The Keap1-Nrf2 system plays a central role in cytoprotection against oxidative and electrophilic insults. Under normal conditions Keap1 serves as a substrate adaptor for Cullin3-based ubiquitin E3 ligase and promotes proteasomal degradation of Nrf2. Keap1 is inactivated upon the exposure to environmental stimuli such as electrophiles, and in this situation Nrf2 is stabilized and activates transcription of cytoprotective genes. Nrf2 knockout mouse (Nrf2–/–) is very sensitive to toxicants like acetaminophen. On the other hand, Keap1 knockdown mouse (Keap1flox/flox) in which Nrf2 is activated is resistant to toxicants. Whereas the turnover of Nrf2 has been well analyzed, little is known about the Keap1 turnover or recovery of the Keap1 activity after the electrophilic insults. We found that Keap1 is accumulated when autophagy is impaired in the liver of mice. Treatment of cells with an autophagy inhibitor or inducer markedly increased or decreased the Keap1 level, respectively. The Keap1 degradation was accelerated upon the exposure to certain type of electrophiles, implying that inactivated Keap1 after modification with electrophiles becomes a preferred substrate of autophagy. We also found that the electrophilic challenge enhances the transcription of Keap1 gene, suggesting that the Keap1 activity is recovered by de novo synthesis of Keap1. Consequently, Keap1 protein was kept in constant level even in the presence of electrophiles. These results thus demonstrate that Keap1 is degraded through autophagy and that this degradation machinery in concert with the de novo synthesis of Keap1 maintains the active Keap1 level and the redox homeostasis regulated by Nrf2.
Constitutive Activation of Nuclear Factor-E2-Related Factor 2 Induces Biotransformation Enzyme and Transporter Expression in Livers of Mice with Hepatocyte-Specific Deletion of Kelch-Like ECH-Associated Protein 1 International-journal Peer-reviewed

Qiuqiong Cheng, Keiko Taguchi, Lauren M. Aleksunes, Jose E. Manautou, Nathan J. Cherrington, Masayuki Yamamoto, Angela L. Slitt

JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY　25　(5)　320-329　2011/09

DOI： 10.1002/jbt.20392 　

ISSN： 1095-6670
Keap1抑制による糸球体硬化症の軽減

清水昭博, 宮田敏男, 田口恵子, 山本雅之, 細谷龍男, 市川家國, 深川雅史, 松阪泰二

日本腎臓学会誌　53　(3)　385-385　2011/05
Publisher: (一社)日本腎臓学会
ISSN： 0385-2385

eISSN： 1884-0728
Initial response and cellular protection through the Keap1/Nrf2 system during the exposure of primary mouse hepatocytes to 1,2-naphthoquinone. International-journal Peer-reviewed

Takashi Miura, Yasuhiro Shinkai, Hai-Yan Jiang, Noriko Iwamoto, Daigo Sumi, Keiko Taguchi, Masayuki Yamamoto, Hideto Jinno, Toshiko Tanaka-Kagawa, Arthur K Cho, Yoshito Kumagai

Chemical research in toxicology　24　(4)　559-67　2011/04/18

DOI： 10.1021/tx100427p 　

ISSN： 0893-228X

eISSN： 1520-5010
Inducible disruption of autophagy in the lung causes airway hyper-responsiveness. International-journal Peer-reviewed

Daisuke Inoue, Hiroshi Kubo, Keiko Taguchi, Takashi Suzuki, Masaaki Komatsu, Hozumi Motohashi, Masayuki Yamamoto

Biochemical and biophysical research communications　405　(1)　13-8　2011/02/04

DOI： 10.1016/j.bbrc.2010.12.092 　

ISSN： 0006-291X
Two-electron quinone reductase (Aldo-keto Reductase 1C Isozyme) augments the oxidative DNA damage induced by quinones in diesel exhaust particles by accelerating redox cycling Peer-reviewed

Shigeru Yamano, Mie Shibata, Hideki Kita, Kimihiko Matsusue, Shizuo Narimatsu, Keiko Taguchi, Yoshito Kumagai

Journal of Health Science　57　(1)　107-114　2011/02

DOI： 10.1248/jhs.57.107 　

ISSN： 1344-9702 1347-5207
Molecular mechanisms of the Keap1–Nrf2 pathway in stress response and cancer evolution. International-journal Peer-reviewed

Keiko Taguchi, Hozumi Motohashi, Masayuki Yamamoto

Genes to cells : devoted to molecular & cellular mechanisms　16　(2)　123-40　2011/02

DOI： 10.1111/j.1365-2443.2010.01473.x 　

ISSN： 1356-9597
Nrf2 counteracts cholestatic liver injury via stimulation of hepatic defense systems

Hirokazu Sugimoto, Kosuke Okada, Junichi Shoda, Keiko Taguchi, Nobuharu Goto, Eiji Warabi, Ichinosuke Hyodo, Tetsuro Ishii, Masayuki Yamamoto

Japanese Pharmacology and Therapeutics　38　(2)　S131-S136　2010/12/25

ISSN： 0386-3603
Ubiquitin accumulation in autophagy-deficient mice is dependent on the Nrf2-mediated stress response pathway: a potential role for protein aggregation in autophagic substrate selection. International-journal Peer-reviewed

Brigit E Riley, Stephen E Kaiser, Thomas A Shaler, Aylwin C Y Ng, Taichi Hara, Mark S Hipp, Kasper Lage, Ramnik J Xavier, Kwon-Yul Ryu, Keiko Taguchi, Masayuki Yamamoto, Keiji Tanaka, Noboru Mizushima, Masaaki Komatsu, Ron R Kopito

The Journal of cell biology　191　(3)　537-52　2010/11/01

DOI： 10.1083/jcb.201005012 　

ISSN： 0021-9525
Nrf2-deficiency creates a responsive microenvironment for metastasis to the lung. International-journal Peer-reviewed

Hironori Satoh, Takashi Moriguchi, Keiko Taguchi, Jun Takai, Jonathan M Maher, Takafumi Suzuki, Paul T Winnard Jr, Venu Raman, Masahito Ebina, Toshihiro Nukiwa, Masayuki Yamamoto

Carcinogenesis　31　(10)　1833-43　2010/10

DOI： 10.1093/carcin/bgq105 　

ISSN： 0143-3334
Genetic analysis of cytoprotective functions supported by graded expression of Keap1. International-journal Peer-reviewed

Keiko Taguchi, Jonathan M Maher, Takafumi Suzuki, Yukie Kawatani, Hozumi Motohashi, Masayuki Yamamoto

Molecular and cellular biology　30　(12)　3016-26　2010/06

DOI： 10.1128/MCB.01591-09 　

ISSN： 0270-7306

eISSN： 1098-5549
The transcriptome of Nrf2-/- mice provides evidence for impaired cell cycle progression in the development of cigarette smoke-induced emphysematous changes. International-journal Peer-reviewed

Stephan Gebel, Svenja Diehl, Jan Pype, Bärbel Friedrichs, Horst Weiler, Jutta Schüller, Haiyan Xu, Keiko Taguchi, Masayuki Yamamoto, Thomas Müller

Toxicological sciences : an official journal of the Society of Toxicology　115　(1)　238-52　2010/05

DOI： 10.1093/toxsci/kfq039 　

ISSN： 1096-6080
The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. International-journal Peer-reviewed

Masaaki Komatsu, Hirofumi Kurokawa, Satoshi Waguri, Keiko Taguchi, Akira Kobayashi, Yoshinobu Ichimura, Yu-Shin Sou, Izumi Ueno, Ayako Sakamoto, Kit I Tong, Mihee Kim, Yasumasa Nishito, Shun-ichiro Iemura, Tohru Natsume, Takashi Ueno, Eiki Kominami, Hozumi Motohashi, Keiji Tanaka, Masayuki Yamamoto

Nature cell biology　12　(3)　213-23　2010/03

DOI： 10.1038/ncb2021 　

ISSN： 1465-7392

eISSN： 1476-4679
Deletion of nuclear factor-E2-related factor-2 leads to rapid onset and progression of nutritional steatohepatitis in mice. International-journal Peer-reviewed

Hirokazu Sugimoto, Kosuke Okada, Junichi Shoda, Eiji Warabi, Kazunori Ishige, Tetsuya Ueda, Keiko Taguchi, Toru Yanagawa, Akira Nakahara, Ichinosuke Hyodo, Tetsuro Ishii, Masayuki Yamamoto

American journal of physiology. Gastrointestinal and liver physiology　298　(2)　G283-94-G294　2010/02

DOI： 10.1152/ajpgi.00296.2009 　

ISSN： 0193-1857
Nrf2 counteracts cholestatic liver injury via stimulation of hepatic defense systems. International-journal Peer-reviewed

Kosuke Okada, Junichi Shoda, Keiko Taguchi, Jonathan M Maher, Kaoru Ishizaki, Yoshimi Inoue, Makio Ohtsuki, Nobuharu Goto, Hirokazu Sugimoto, Hirotoshi Utsunomiya, Koji Oda, Eiji Warabi, Tetsuro Ishii, Masayuki Yamamoto

Biochemical and biophysical research communications　389　(3)　431-6　2009/11/20

DOI： 10.1016/j.bbrc.2009.08.156 　

ISSN： 0006-291X
1-Cyano-2,3-epithiopropane is a novel plant-derived chemopreventive agent which induces cytoprotective genes that afford resistance against the genotoxic alpha,beta-unsaturated aldehyde acrolein. International-journal Peer-reviewed

Michael O Kelleher, Michael McMahon, Ian M Eggleston, Mark J Dixon, Keiko Taguchi, Masayuki Yamamoto, John D Hayes

Carcinogenesis　30　(10)　1754-62　2009/10

DOI： 10.1093/carcin/bgp182 　

ISSN： 0143-3334
Oxidative Stress More Strongly Induced by ortho- Than para-quinoid Polycyclic Aromatic Hydrocarbons in A549 Cells Peer-reviewed

Yumi Motoyama, Kanae Bekki, Sang Woon Chung, Ning Tang, Takayuki Kameda, Akira Toriba, Keiko Taguchi, Kazuichi Hayakawa

JOURNAL OF HEALTH SCIENCE　55　(5)　845-850　2009/10

DOI： 10.1248/jhs.55.845 　

ISSN： 1344-9702
Oxidative Stress-Dependent Cellular Toxicity and Cytoprotection during Exposure to 9,10-phenanthraquinone, a Component of Diesel Exhaust Particles Invited Peer-reviewed

Keiko Taguchi

JOURNAL OF HEALTH SCIENCE　55　(3)　347-350　2009/06

DOI： 10.1248/jhs.55.347 　

ISSN： 1344-9702
Genetic versus chemoprotective activation of Nrf2 signaling: overlapping yet distinct gene expression profiles between Keap1 knockout and triterpenoid-treated mice. International-journal Peer-reviewed

Melinda S Yates, Quynh T Tran, Patrick M Dolan, William O Osburn, Soona Shin, Colin C McCulloch, Jay B Silkworth, Keiko Taguchi, Masayuki Yamamoto, Charlotte R Williams, Karen T Liby, Michael B Sporn, Thomas R Sutter, Thomas W Kensler

Carcinogenesis　30　(6)　1024-31　2009/06

DOI： 10.1093/carcin/bgp100 　

ISSN： 0143-3334
Nrf2 counteracts cholestatic liver injury via stimulation of hepatic defense systems International-journal Peer-reviewed

Kosuke Okada, Junichi Shoda, Keiko Taguchi, Jonathan M. Maher, Kaoru Ishizaki, Yoshimi Inoue, Makio Ohtsuki, Nobuharu Goto, Hirokazu Sugimoto, Hirotoshi Utsunomiy, Koji Oda, Eiji Warabi, Tetsuro Ishii, Masayuki Yamamoto

Biochemical and Biophysical Research Communications　389　(3)　431-436　2009
Publisher: Academic Press Inc.
DOI： 10.1016/j.bbrc.2009.08.156 　

ISSN： 1090-2104 0006-291X
Ursodeoxycholic acid stimulates Nrf2-mediated hepatocellular transport, detoxification, and antioxidative stress systems in mice. International-journal Peer-reviewed

Kosuke Okada, Junichi Shoda, Keiko Taguchi, Jonathan M Maher, Kaoru Ishizaki, Yoshimi Inoue, Makio Ohtsuki, Nobuharu Goto, Koichi Takeda, Hirotoshi Utsunomiya, Koji Oda, Eiji Warabi, Tetsuro Ishii, Keiko Osaka, Ichinosuke Hyodo, Masayuki Yamamoto

American journal of physiology. Gastrointestinal and liver physiology　295　(4)　G735-47-G747　2008/10

DOI： 10.1152/ajpgi.90321.2008 　

ISSN： 0193-1857
Genetic or pharmacologic amplification of nrf2 signaling inhibits acute inflammatory liver injury in mice. International-journal Peer-reviewed

William O Osburn, Melinda S Yates, Patrick D Dolan, Sining Chen, Karen T Liby, Michael B Sporn, Keiko Taguchi, Masayuki Yamamoto, Thomas W Kensler

Toxicological sciences : an official journal of the Society of Toxicology　104　(1)　218-27　2008/07

DOI： 10.1093/toxsci/kfn079 　

ISSN： 1096-6080
Redox cycling of 9,10-phenanthraquinone to cause oxidative stress is terminated through its monoglucuronide conjugation in human pulmonary epithelial A549 cells. International-journal Peer-reviewed

Keiko Taguchi, Megumi Shimada, Sayako Fujii, Daigo Sumi, Xiaoqing Pan, Shigeru Yamano, Takahito Nishiyama, Akira Hiratsuka, Masayuki Yamamoto, Arthur K Cho, John R Froines, Yoshito Kumagai

Free radical biology & medicine　44　(8)　1645-55　2008/04/15

DOI： 10.1016/j.freeradbiomed.2008.01.024 　

ISSN： 0891-5849

eISSN： 1873-4596
Ursodeoxycholic acid exerts Nrf2-mediated stimulation of hepatobiliary transport, detoxification and antioxidative stress systems. Peer-reviewed

Okada;K, Shoda;J, Taguchi;K, Goto;N, Takeda;K, Utsunomiya;H, Oda;K, Warabi;E, Ishii;T, Osaka;K, Yamamoto;M, 正田, 純一

Am J Physiol　295　G735-G747　2008/01
Cytoprotective role of Nrf2/Keap1 system in methylmercury toxicity. International-journal Peer-reviewed

Takashi Toyama, Daigo Sumi, Yasuhiro Shinkai, Akira Yasutake, Keiko Taguchi, Kit I Tong, Masayuki Yamamoto, Yoshito Kumagai

Biochemical and biophysical research communications　363　(3)　645-50　2007/11/23

DOI： 10.1016/j.bbrc.2007.09.017 　

ISSN： 0006-291X
An approach to evaluate two-electron reduction of 9,10-phenanthraquinone and redox activity of the hydroquinone associated with oxidative stress International-journal Peer-reviewed

Keiko Taguchi, Sayako Fujii, Shigeru Yamano, Arthur K. Cho, Shinji Kamisuki, Yumi Nakai, Fumio Sugawara, John R. Froines, Yoshito Kumagai

FREE RADICAL BIOLOGY AND MEDICINE　43　(5)　789-799　2007/09

DOI： 10.1016/j.freeradbiomed.2007.05.021 　

ISSN： 0891-5849

eISSN： 1873-4596
Toxicological effects of polycyclic aromatic hydrocarbon quinones contaminated in diesel exhaust particles Invited Peer-reviewed

Yoshito Kumagai, Keiko Taguchi

Asian Journal of Atmospheric Environment　1　(1)　28-35　2007
Publisher: Korean Society for Atmospheric Environment
DOI： 10.5572/ajae.2007.1.1.028 　

ISSN： 2287-1160 1976-6912
Inhibition of endothelial nitric oxide synthase activity and suppression of endothelium-dependent vasorelaxation by 1,2-naphthoquinone, a component of diesel exhaust particles International-journal Peer-reviewed

Y Sun, K Taguchi, D Sumi, S Yamano, Y Kumagai

ARCHIVES OF TOXICOLOGY　80　(5)　280-285　2006/05

DOI： 10.1007/s00204-005-0043-3 　

ISSN： 0340-5761
1,2-naphthoquinone activates vanilloid receptor 1 through increased protein tyrosine phosphorylation, leading to contraction of guinea pig trachea International-journal Peer-reviewed

S Kikuno, K Taguchi, N Iwamoto, S Yamano, AK Cho, Froines, JR, Y Kumagai

TOXICOLOGY AND APPLIED PHARMACOLOGY　210　(1-2)　47-54　2006/01

DOI： 10.1016/j.taap.2005.06.015 　

ISSN： 0041-008X
The interactions of 9,10-phenanthrenequinone with glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a potential site for toxic actions International-journal Peer-reviewed

CE Rodriguez, JM Fukuto, K Taguchi, J Froines, AK Cho

CHEMICO-BIOLOGICAL INTERACTIONS　155　(1-2)　97-110　2005/06

DOI： 10.1016/j.cbi.2005.05.002 　

ISSN： 0009-2797

eISSN： 1872-7786
Monomethylarsonous acid inhibits endothelial nitric oxide synthase activity Peer-reviewed

Daigo Sumi, Keiko Taguchi, Yang Sun, Yasuhiro Shinkai, Yoshito Kumagai

Journal of Health Science　51　(6)　728-730　2005
Publisher: Pharmaceutical Society of Japan
DOI： 10.1248/jhs.51.728 　

ISSN： 1347-5207 1344-9702
Decreased enzyme activity of hepatic thioredoxin reductase and glutathione reductase in rabbits by prolonged exposure to inorganic arsenate International-journal Peer-reviewed

M Nikaido, JB Pi, Y Kumagai, H Yamauchi, K Taguchi, S Horiguchi, Y Sun, GF Sun, N Shimojo

ENVIRONMENTAL TOXICOLOGY　18　(5)　306-311　2003/10

DOI： 10.1002/tox.10129 　

ISSN： 1520-4081
Oxidative-stress-inducible qorA encodes an NADPH-dependent quinone oxidoreductase catalysing a one-electron reduction in Staphylococcus aureus International-journal Peer-reviewed

A Maruyama, Y Kumagai, K Morikawa, K Taguchi, H Hayashi, T Ohta

MICROBIOLOGY-SGM　149　(Pt 2)　389-398　2003/02

DOI： 10.1099/mic.0.25796-0 　

ISSN： 1350-0872
Oxidation of proximal protein sulfhydryls by phenanthraquinone, a component of diesel exhaust particles International-journal Peer-reviewed

Y Kumagai, S Koide, K Taguchi, A Endo, Y Nakai, T Yoshikawa, N Shimojo

CHEMICAL RESEARCH IN TOXICOLOGY　15　(4)　483-489　2002/04

DOI： 10.1021/tx0100993 　

ISSN： 0893-228X
Oxidative stress-inducible qorA encodes an NADPH-dependent quinone oxidoreductase catalyzing a one-electron reduction in Staphylococcus aureus(jointly worked) Peer-reviewed

Maruyama, Atsushi, Kumagai, Yoshito, Morikawa, Kazuya, Taguchi, Keiko, Hayashi, Hideo, Ohta, Toshiko

Microbiology (Reading, England)　149　(Pt 2)　389-398　2002/02

ISSN： 1465-2080

More details Close

This work characterized the putative quinone oxidoreductase gene (qorA) from Staphylococcus aureus. The deduced amino acid sequence indicated that the 333 aa protein contains an NAD(P)H-binding motif. A Northern blot analysis revealed that 2.6 kb and 1.4 kb signals were detected by using a qorA probe. Both the signals were enhanced under the presence of a redox-cycling agent, 9,10-phenanthrenequinone (PQ). It was also revealed that the expression of three genes, SA1988, SA1989 (qorA) and SA1990, was enhanced at the transcriptional level by PQ exposure. The results suggested that the 2.6 kb signal detected by the qorA probe was in two co-transcripts, i.e. SA1990-qorA and qorA-SA1988 were transcribed. Besides, primer extension analyses confirmed the enhancement of qorA and SA1990 transcripts. The GST (glutathione S-transferase)-tagged QorA protein was expressed in Escherichia coli and purified using a glutathione affinity column. In purification steps, a 36 kDa band co-purified with the GST-QorA, and it was detected even in the thrombin-cleaved fraction. N-terminal amino acid sequences for the 36 kDa protein revealed that it was an intact QorA. They showed that QorA formed a multimer
Phenanthraquinone affects endothelial nitric oxide synthase activity through modification of the thiol group: An alternative inhibition mechanism Peer-reviewed

Keiko Taguchi, Yoshito Kumagai, Akiko Endo, Makoto Kikushima, Yuji Ishii, Nobuhiro Shimojo

Journal of Health Science　47　(6)　571-574　2001

DOI： 10.1248/jhs.47.571 　

ISSN： 1344-9702

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Misc. 128

Study on the activation of Nrf2 system in thioacetamide-induced GSTp-positive hepatocyte foci

伊藤ゆり, 井澤武史, 濱田菜々子, 田中美有, 田口恵子, 田口恵子, 山本雅之, 桑村充

日本毒性病理学会総会及び学術集会講演要旨集　40th　2024
食道扁平上皮癌細胞におけるNRF2とNQO1の発現とゲルダナマイシン誘導体の増殖抑制

押切裕之, 押切裕之, 田口恵子, 谷山裕亮, 山本雅之, 亀井尚

日本食道学会学術集会抄録集(CD-ROM)　78th　2024
NRF2-addicted Cancer: From Classical Experimental Animal Models toward Diagnosis and Treatment

田口恵子

Journal of Toxicological Sciences　48　(Supplement (CD-ROM))　2023

ISSN： 0388-1350
Nrf2 and iron metabolism in liver tumorigenesis

田口恵子, 田口恵子, 田口恵子

肝胆膵　84　(4)　2022

ISSN： 0389-4991
細胞競合によるNRF2活性化細胞の排除機構

廣瀬亘, 堀内真, 田口恵子, 谷山裕亮, 山本雅之, 亀井尚

日本食道学会学術集会抄録集(CD-ROM)　76th　2022
鉄過剰による化合物誘発肝硬変の抑制に関わる転写因子Nrf2の役割

濱田菜々子, 井澤武史, 新真智, 瓶井知美, 藤原奨, 田中美有, 田口恵子, 山本雅之, 桑村充

日本獣医学会学術集会講演要旨集　165th (CD-ROM)　2022

ISSN： 1347-8621
AhR and Atopic Dermatitis

枝光智大, 田口恵子, 山本雅之

Journal of Toxicological Sciences　47　(Supplement (CD-ROM))　2022

ISSN： 0388-1350
Molecular Mechanism of Environmental Response and Adaptation

田口恵子, 田口恵子, 田口恵子, 山本雅之, 山本雅之, 山本雅之

日本体質医学会雑誌　83　(1)　2021

ISSN： 1347-7137
Keap1-Nrf2システムによる生体機能制御機構の解明

田口恵子

東北医学雑誌　132　(1)　2020

ISSN： 0040-8700
Keap1-Nrf2 system and liver toxicology

田口恵子, 山本雅之

Journal of Toxicological Sciences　45　(Supplement)　2020

ISSN： 0388-1350
ラット腹膜中皮細胞におけるNrf2-Keap1システムの意義

矢花郁子, 高橋知香, 廣瀬卓男, 田口恵子, 山本雅之, 森建文

日本透析医学会雑誌　53　(Supplement 1)　2020

ISSN： 1340-3451
Nrf2欠損はマウス急性膵炎モデルにおいて炎症を増悪させるか

鍋島立秀, 濱田晋, 田口恵子, 田中裕, 松本諒太郎, 山本雅之, 正宗淳

日本消化器病学会雑誌　116　(臨増総会)　A263-A263　2019/03
Publisher: (一財)日本消化器病学会
ISSN： 0446-6586

eISSN： 1349-7693
Nrf2欠損はマウス急性膵炎モデルにおいて炎症を増悪させるか

鍋島立秀, 濱田晋, 田口恵子, 田中裕, 松本諒太郎, 山本雅之, 正宗淳

日本消化器病学会雑誌(Web)　116　2019

ISSN： 1349-7693
Bag-1はGSH合成阻害剤BSO存在下における細胞増殖と細胞内GSHレベルの低下に寄与する

猪瀬(丸山)敦史, 猪瀬(丸山)敦史, 田口恵子, 守田匡伸, 山本雅之, 久下周佐

日本生化学会大会(Web)　92nd　2019
肺移植後虚血再灌流肺障害におけるNrf2活性化の効果

東郷威男, 星川康, 田口恵子, 矢吹皓, 三友英紀, 渡邊龍秋, 松田安史, 大石久, 佐渡哲, 野田雅史, 舟橋淳一, 山本雅之, 岡田克典

移植　53　(総会臨時)　398-398　2018/09
Publisher: (一社)日本移植学会
ISSN： 0578-7947
肺移植後虚血再灌流肺障害におけるNrf2活性化の効果

東郷威男, 星川康, 田口恵子, 矢吹皓, 三友英紀, 渡邊龍秋, 松田安史, 大石久, 佐渡哲, 野田雅史, 舟橋淳一, 山本雅之, 岡田克典

移植　53　(総会臨時)　398-398　2018/09
Publisher: (一社)日本移植学会
ISSN： 0578-7947
AhRによる神経栄養因子アルテミンの発現誘導が惹起するアトピー性皮膚炎の痒み過敏

枝光智大, 枝光智大, 田口恵子, 小林枝里, 奥山隆平, 山本雅之

日本生化学会大会(Web)　91st　2018
肺移植後虚血再灌流肺障害における抗酸化ストレス転写因子Nrf2の役割の検討

東郷威男, 星川康, 田口恵子, 矢吹皓, 三友英紀, 渡邊龍秋, 野田雅史, 松田安史, 大石久, 佐渡哲, 船橋淳一, 山本雅之, 岡田克典

日本肺および心肺移植研究会プログラム・抄録集　34th　2018
慢性炎症から肝胆膵癌にいたるランドスケープ総論生体防御機構Keap1-Nrf2システムの視点から

田口恵子

肝胆膵　77　(3)　2018

ISSN： 0389-4991
活性酸素種センサーBag-1遺伝子エキソン5領域欠失のマウス個体におよぼす影響解析

猪瀬(丸山)敦史, 田口恵子, 守田匡伸, 山本雅之, 久下周佐

日本生化学会大会(Web)　91st　2018
オートファジーの異常は転写調節を介して代謝再編成を引き起こす

齊藤哲也, 一村義信, 田口恵子, 藤村務, 上野隆, 本橋ほづみ, 和栗聡, 曽我朋義, 山本雅之, 田中啓二, 小松雅明

がんと代謝研究会プログラム&抄録集　5th　60　2017/07
オートファジーによる細胞死の制御オートファジーとKeap1-Nrf2システム

田口恵子, 小松雅明, 山本雅之

The Journal of Toxicological Sciences　42　(Suppl.)　S143-S143　2017/06
Publisher: (一社)日本毒性学会
ISSN： 0388-1350
SIMULTANEOUS ACTIVATION OF K-RAS AND NRF2 INDUCE PANCREATIC ATROPHY

Shin Hamada, Atsushi Masamune, Keiko Taguchi, Masayuki Yamamoto, Tooru Shimosegawa

GASTROENTEROLOGY　152　(5)　S894-S894　2017/04

ISSN： 0016-5085

eISSN： 1528-0012
大気汚染がアトピー性皮膚炎を引き起こす分子メカニズム

枝光智大, 田口恵子, 山本雅之

感染・炎症・免疫　47　(3)　2017

ISSN： 0387-1010
Pten欠失肝臓がんにおけるNrf2活性獲得の意義

田口恵子, 一戸理沙, 山本雅之

がんと代謝研究会プログラム&抄録集　5th　2017
毒性学における転写因子Nrf2の貢献

田口恵子

Journal of Toxicological Sciences　42　(Supplement)　2017

ISSN： 0388-1350
オートファジーの破綻による肝腫瘍とKeap1-Nrf2システム

田口恵子, 小松雅明, 山本雅之

日本生化学会大会プログラム・講演要旨集　89回　[3P-025]　2016/09
Publisher: (公社)日本生化学会
NRF2 Knockout Suppresses Pancreatic Carcinogenesis in a Mouse Model

Shin Hamada, Atsushi Masamune, Keiko Taguchi, Masayuki Yamamoto, Tooru Shimosegawa

GASTROENTEROLOGY　150　(4)　S163-S163　2016/04

ISSN： 0016-5085

eISSN： 1528-0012
エストロゲンはNrf2を介して逆流性食道炎を抑制する

鳥畑勇大, 淺沼清孝, 田口恵子, 浅野直喜, 今谷晃, 山本雅之, 下瀬川徹

日本消化器病学会大会(Web)　58th　2016
二つのタンパク質分解系による統合的なNrf2の制御メカニズム

田口恵子

生化学　88　(5)　2016

ISSN： 0037-1017
Keap1欠失によるNrf2非依存的なPten発現上昇と肝病態抑制

一戸理沙, 田口恵子, 山本雅之

日本生化学会大会(Web)　89th　2016
Nrf2はPten欠失による脂肪肝炎から肝臓がんへの進展に関与する

一戸理沙, 田口恵子, 山本雅之

衛生薬学・環境トキシコロジー講演要旨集　2016　2016

ISSN： 0919-2115
Nrf2はヘム合成阻害剤による肝毒性を防御する

増井紗帆, 田口恵子, 山本雅之

衛生薬学・環境トキシコロジー講演要旨集　2016　2016

ISSN： 0919-2115
p62/Sqstm1はNrf2依存的代謝再編成により肝細胞がんの悪性化をもたらす

齊藤哲也, 一村義信, 田口恵子, 藤村務, 上野隆, 若井俊文, 本橋ほづみ, 和栗聡, 曽我朋義, 山本雅之, 田中啓二, 小松雅明

がんと代謝研究会プログラム&抄録集　4th　2016
p62/Sqstm1はNrf2依存的代謝再編成により肝細胞がんの悪性化をもたらす

齊藤哲也, 一村義信, 田口恵子, 鈴木隆史, 水島恒裕, 藤村務, 上野隆, 大江知之, 増野匡彦, 若井俊文, 岡部隆義, 長野哲雄, 本橋ほづみ, 和栗聡, 曽我朋義, 山本雅之, 田中啓二, 小松雅明

日本分子生物学会年会プログラム・要旨集(Web)　39th　2016
オートファジーの抑制は代謝および転写リプログラミングを引き起こす

斉藤哲也, 和栗聡, 藤村務, 上野隆, 田口恵子, 本橋ほづみ, 山本雅之, 曽我朋義, 田中啓二, 小松雅明

日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　88回・38回　[2P0443]-[2P0443]　2015/12
Publisher: (公社)日本生化学会
肝疾患における転写因子Nrf2の機能変化

田口恵子

Bio Clinica　2015

ISSN： 0919-8237
オートファジー障害に伴う糖,アミノ酸代謝再編成

斉藤哲也, 斉藤哲也, 斉藤哲也, 和栗聡, 藤村務, 上野隆, 田口恵子, 本橋ほづみ, 山本雅之, 曽我朋義, 田中啓二, 小松雅明

がんと代謝研究会プログラム&抄録集　3rd　2015
Nrf2はPten欠失による脂肪肝炎から肝がんへの移行を促進する

田口恵子, 一戸理沙, 山本雅之

がんと代謝研究会プログラム&抄録集　3rd　2015
タンパク質分解によるNrf2活性制御メカニズム

田口恵子, 田口恵子, 本橋ほづみ, 山本雅之

日本薬学会年会要旨集(CD-ROM)　135th　2015
Nrf2はPten欠失による脂肪肝炎から肝臓がんの移行を促進する

田口恵子, 一戸理沙, 山本雅之

日本生化学会大会(Web)　88th　2015
PS-083-8 マウス門脈枝結紮後の代償的肝肥大におけるNrf2の役割(PS-083 肝基礎-3,ポスターセッション,第114回日本外科学会定期学術集会)

白崎圭一, 藪内伸一, 田口恵子, 川口桂, 唐澤秀明, 青木豪, 深瀬耕二, 水間正道, 坂田直昭, 中川圭, 林洋毅, 岡田恭穂, 森川孝則, 吉田寛, 元井冬彦, 内藤剛, 片寄友, 江川新一, 本橋ほづみ, 山本雅之, 海野倫明

日本外科学会雑誌　115　(2)　741-741　2014/03/05
Publisher: 一般社団法人日本外科学会
ISSN： 1880-1129
マウス門脈枝結紮後の代償的肝肥大におけるNrf2の役割

白崎圭一, 藪内伸一, 田口恵子, 川口桂, 唐澤秀明, 青木豪, 深瀬耕二, 水間正道, 坂田直昭, 中川圭, 林洋毅, 岡田恭穂, 森川孝則, 吉田寛, 元井冬彦, 内藤剛, 片寄友, 江川新一, 橋本ほづみ, 山本雅之, 海野倫明

日本外科学会雑誌　115　(臨増2)　741-741　2014/03
Publisher: (一社)日本外科学会
ISSN： 0301-4894
オートファジー障害に伴う糖,アミノ酸代謝再編成

斉藤哲也, 斉藤哲也, 斉藤哲也, 曽友深, 和栗聡, 藤村務, 上野隆, 田口恵子, 本橋ほづみ, 山本雅之, 田中啓二, 曽我朋義, 小松雅明

日本分子生物学会年会プログラム・要旨集(Web)　37th　2014
代謝と癌-oncogenic metabolism研究の進歩-癌細胞のグルコース・グルタミン代謝異常と癌遺伝子異常はどのように関連づけられるか

光石陽一郎, 田口恵子

分子消化器病　11　(4)　2014

ISSN： 1348-995X
Nrf2の活性制御破綻がもたらす肝病態

田口恵子, 田口恵子, 本橋ほづみ, 山本雅之

日本生化学会大会(Web)　87th　2014
肝毒性物質による肝肥大における転写因子Nrf2の役割

田口恵子, 田口恵子, 本橋ほづみ, 伊藤暢, 田中稔, 宮島篤, 山本雅之

衛生薬学・環境トキシコロジー講演要旨集　2013　2013

ISSN： 0919-2115
細胞増殖におけるKeap1-Nrf2酸化ストレス応答機構の役割

本橋ほづみ, 白崎圭一, 白崎圭一, 白崎圭一, 光石陽一郎, 光石陽一郎, 田口恵子, 田口恵子, 山本雅之

がんと代謝研究会プログラム&抄録集　1st　2013
門脈枝結紮による代償的肝肥大におけるNrf2の役割

白崎圭一, 白崎圭一, 白崎圭一, 田口恵子, 本橋ほづみ, 海野倫明, 山本雅之

日本生化学会大会(Web)　86th　2013
細胞増殖におけるKeap1-Nrf2酸化ストレス応答機構の役割

本橋ほづみ, 白崎圭一, 白崎圭一, 白崎圭一, 光石陽一郎, 光石陽一郎, 田口恵子, 田口恵子, 山本雅之

日本分子生物学会年会プログラム・要旨集(Web)　36th　2013
角膜上皮創傷治癒におけるNrf2の役割

林竜平, 檜森紀子, 田口恵子, 石川幸, 上杉晃司, 伊藤美由紀, DUNCAN Thomas, 中澤徹, 山本雅之, 西田幸二

日本眼科学会雑誌　117　2013

ISSN： 0029-0203
転写因子Nrf2はグルコースとグルタミンの代謝を変化させ代謝のリプログラミングを促進する (ライフサイエンス新着論文レビュー)

光石陽一郎, 田口恵子, 本橋ほづみ

ライフサイエンス新着論文レビュー　1　2012/07/19
酸化ストレス研究における網膜神経節細胞純化回収法の確立

檜森紀子, 田口恵子, 劉孟林, 安田正幸, 横山悠, 相澤奈帆子, 面高宗子, 山本雅之, 中澤徹

日本眼科学会雑誌　116　(臨増)　303-303　2012/03
Publisher: (公財)日本眼科学会
ISSN： 0029-0203
マウス網膜神経節細胞障害時におけるHO-1

檜森紀子, 檜森紀子, 田口恵子, 山本雅之, 中澤徹

日本緑内障学会抄録集　23rd　2012
転写因子Nrf2はペントースリン酸経路とグルタミン代謝を制御して細胞増殖に貢献する

光石陽一郎, 光石陽一郎, 田口恵子, 油谷浩幸, 貫和敏博, 本橋ほづみ, 山本雅之

日本呼吸器学会誌　1　2012

ISSN： 2186-5876
シグナル伝達機構研究の最前線 7.活性酸素種や親電子性物質によるシグナル伝達

田口恵子, 山本雅之

実験医学　30　(5)　2012

ISSN： 0288-5514
肝臓における2つのNrf2活性制御機構と胆管形成

田口恵子, 本橋ほづみ, 山本雅之

衛生薬学・環境トキシコロジー講演要旨集　2012　2012

ISSN： 0919-2115
がん細胞における酸化ストレス応答機構の役割と代謝リプログラミングへの貢献

光石陽一郎, 光石陽一郎, 田口恵子, 山本雅之, 本橋ほづみ

日本生化学会大会(Web)　85th　2012
肝臓における2つのNrf2活性制御機構と胆管形成

田口恵子, 本橋ほづみ, 山本雅之

日本生化学会大会(Web)　85th　2012
マウス網膜神経節細胞障害における網膜神経節細胞純化回収法の確立

檜森紀子, 田口恵子, 山本雅之, 中澤徹

日本抗加齢医学会総会プログラム・抄録集　12th　2012
代謝リプログラミングにおける酸化ストレス応答機構の役割（実験医学） Invited Peer-reviewed

田口恵子, 本橋ほづみ

実験医学　30　(17)　2814-2821　2012

ISSN： 0288-5514
Nrf2-Keap1生体防御システムの機能とその破綻による病態の解明 (東北醫学雑誌)

田口恵子

東北醫学雑誌　123　(1)　51-54　2011/06

ISSN： 0040-8700
マウス網膜神経節細胞障害におけるNrf2の役割

檜森紀子, 中澤徹, 田口恵子, 劉孟林, 安田正幸, 面高宗子, シャナブ・アフメド, 山本雅之

日本眼科学会雑誌　115　(臨増)　252-252　2011/04
Publisher: (公財)日本眼科学会
ISSN： 0029-0203
転写因子Nrf2はペントースリン酸経路とグルタミン代謝を制御して細胞増殖に貢献する

光石陽一郎, 田口恵子, 油谷浩幸, 貫和敏博, 本橋ほづみ, 山本雅之

生化学　2011

ISSN： 0037-1017
転写因子Nrf2の活性制御タンパク質Keap1の分解と合成

田口恵子, 藤川奈々子, 本橋ほづみ, 山本雅之

衛生薬学・環境トキシコロジー講演要旨集　2011　2011

ISSN： 0919-2115
角膜上皮創傷治時におけるNrf2を介した酸化ストレス防御機構の役割

林竜平, 檜森紀子, 田口惠子, 伊藤美由紀, 山本雅之, 西田幸二

日本眼科学会雑誌　115　2011

ISSN： 0029-0203
Nrf2 activates the pentose phosphate pathway and glutamine consumption in proliferating cells

Yoichiro Mitsuishi, Keiko Taguchi, Masayuki Yamamoto, Hozumi Motohashi

INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE　28　S16-S16　2011

ISSN： 1107-3756
Keap1 degradation by autophagy for the maintenance of redox homeostasis

Nanako Fujikawa, Keiko Taguchi, Hozumi Motohashi, Masayuki Yamamoto

INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE　28　S75-S75　2011

ISSN： 1107-3756
転写因子Nrf2欠損はウレタン誘導性肺発癌を減少させNrf2欠損癌組織は免疫不全マウスで著しい生着不全と増殖能低下をきたす.

佐藤大希, 森口尚, 田口恵子, 海老名雅仁, 貫和敏博, 山本雅之

日本癌学会総会記事　70回　150-150　2011
Publisher: (一社)日本癌学会
ISSN： 0546-0476
宿主におけるNrf2欠損はMDSCs細胞に著明な酸化ストレスの蓄積を誘導し、肺癌転移に対して有利な微小環境を創造する(Nrf2-deficiency creates a responsive microenvironment for metastasis to the lung by MDSCs ROS accumulation)

佐藤大希, 森口尚, 田口恵子, 海老名雅仁, 貫和敏博, 山本雅之

日本癌学会総会記事　69回　137-137　2010/08
Publisher: (一社)日本癌学会
ISSN： 0546-0476
上皮細胞における転写因子Nrf2の活性化

田口恵子, 鈴木隆史, 本橋ほづみ, 山本雅之

生化学　82　(7)　2010

ISSN： 0037-1017
上皮細胞における転写因子Nrf2の活性化

田口恵子, 鈴木隆史, 本橋ほづみ, 山本雅之

衛生薬学・環境トキシコロジー講演要旨集　2010　2010

ISSN： 0919-2115
総胆管結紮による急性胆汁うっ滞におけるKeap1-Nrf2systemの役割

杉本浩一, 岡田浩介, 正田純一, 蕨栄治, 田口恵子, 宇都宮洋才, 小田高司, 後藤信冶, 兵頭一之介, 石井哲郎, 山本雅之

肝臓　51　(Supplement 1)　2010

ISSN： 0451-4203
総胆管結紮による急性胆汁うっ滞におけるKeap1-Nrf2Systemの役割

杉本浩一, 岡田浩介, 兵頭一之介, 正田純一, 蕨栄治, 石井哲郎, 田口恵子, 山本雅之, 後藤信治

薬理と治療　38　(Suppl.2)　2010

ISSN： 0386-3603
転写因子Nrf2は宿主肺における癌転移抑制性因子である

佐藤大希, 田口恵子, 森口尚, 海老名雅仁, 貫和敏博, 山本雅之

日本呼吸器学会雑誌　48　(増刊)　151-151　2010
Publisher: (一社)日本呼吸器学会
ISSN： 1343-3490
転写因子Nrf2はコリンメチオニン欠乏食(MCDD)誘発非アルコール性脂肪性肝炎(NASH)を防御する

杉本浩一, 岡田浩介, 正田純一, 蕨栄治, 柳川徹, 田口恵子, 兵頭一之介, 石井哲郎, 山本雅之

肝臓　50　(Supplement 2)　2009

ISSN： 0451-4203
転写因子Nrf2はコリンメチオニン欠乏食(MCDD)誘発非アルコール性脂肪性肝炎(NASH)を防御する

杉本浩一, 岡田浩介, 正田純一, 蕨栄治, 柳川徹, 田口恵子, 兵頭一之介, 石井哲郎, 山本雅之

肝臓　50　(Supplement 1)　2009

ISSN： 0451-4203
親電子性環境化学物質1,2-ナフトキノンの毒性発現におけるNrf2/Keap1システムの役割

三浦高, 角大悟, 姜海燕, 田口恵子, 山本雅之, 熊谷嘉人, 熊谷嘉人

日本薬学会年会要旨集　129th　(1)　2009

ISSN： 0918-9823
Nrf2は肺における新規転移抑制因子として働く

佐藤大希, 田口恵子, 森口尚, 鈴木隆史, 海老名雅仁, 貫和敏博, 山本雅之

日本癌学会総会記事　68回　248-248　2009
Publisher: (一社)日本癌学会
ISSN： 0546-0476
酸化ストレスを生じるディーゼル排出微粒子成分の毒性発現と生体防御機構の解明

田口恵子

衛生薬学・環境トキシコロジー講演要旨集　2008　2008

ISSN： 0919-2115
閉塞性胆汁うっ滞において転写因子Nrf2は生体防御の役割を果たす

杉本浩一, 岡田浩介, 正田純一, 兵頭一之介, 田口恵子, 山本雅之, 蕨栄治, 石井哲郎, 武田公一, 宇都宮洋才, 小田高司, 後藤信冶

胆汁酸研究会プログラム・抄録集　30th　2008
UDCAは転写因子Nrf2を活性化し,肝細胞の輸送,解毒代謝,抗酸化ストレス応答を賦活する

岡田浩介, 正田純一, 田口恵子, 蕨栄治, 宇都宮洋才, 小田高司, 後藤信治, 石井哲郎, 山本雅之, 兵頭一之介

肝臓　49　(Supplement 1)　2008

ISSN： 0451-4203
分子毒性学における転写因子研究:Nrf2活性化が生体に及ぼす正負の作用

田口恵子

生化学　2008

ISSN： 0037-1017
酸化ストレス防御のための生体内センサー (日本農芸化学会『化学と生物』)

田口恵子, 山本雅之

日本農芸化学会『化学と生物』　45　(12)　--862　2007/12
Publisher: Japan Society for Bioscience, Biotechnology, and Agrochemistry
DOI： 10.1271/kagakutoseibutsu1962.45.857 　

ISSN： 0453-073X
酸化ストレスの原因となる大気中多環芳香族炭化水素 (環境ホルモン学会『ニュースレター』)

田口恵子, 熊谷嘉人

環境ホルモン学会『ニュースレター』　9　(4)　-　2007/09
インチンコウ湯は転写因子Nrf2を活性化し,生体の抗酸化ストレス応答機構を賦活する

岡田浩介, 正田純一, 兵頭一之介, 石井哲郎, 大嶽信弘, 鈴木祥子, 山本雅浩, 田口恵子, 山本雅之

日本消化器病学会雑誌　104　2007

ISSN： 0446-6586
恒常的なNrf2活性化によるアセトアミノフェン毒性発現の防御

田口恵子, MAHER Jonathan M., 川谷幸恵, 鈴木隆史, 山本雅之

Journal of Toxicological Sciences　32　(Supplement)　2007

ISSN： 0388-1350
Nrf2/Keap1システムは神経細胞においてメチル水銀の解毒を促す

外山喬士, 角大悟, 角大悟, 新開泰弘, 田口恵子, 山本雅之, 山本雅之, 熊谷嘉人, 熊谷嘉人

Journal of Toxicological Sciences　32　(Supplement)　2007

ISSN： 0388-1350
1,2-ナフトキノンの解毒に関わるNrf2/Keap1システムの役割

JIANG Hai-Yan, 角大悟, 田口恵子, TONG Kit I., 山本雅之, 熊谷嘉人, 熊谷嘉人

衛生薬学・環境トキシコロジー講演要旨集　2007　2007

ISSN： 0919-2115
Keap1遺伝子部分破壊によるNrf2抑制破綻の表現型解析

田口恵子, PFEIFFER Martin J., MAHER Jonathan M., 川谷幸恵, 鈴木隆史, 山本雅之

衛生薬学・環境トキシコロジー講演要旨集　2007　2007

ISSN： 0919-2115
酸化ストレス防御のための生体内センサー Keap1-Nrf2制御システム

田口恵子, 田口恵子, 山本雅之, 山本雅之

化学と生物　45　(12)　2007

ISSN： 0453-073X
胆汁うっ滞症における肝輸送蛋白の発現異常と分子標的薬物療法

正田純一, 岡田浩介, 石井哲郎, 田口恵子, 山本雅之

日本薬学会年会要旨集　127th　(1)　2007

ISSN： 0918-9823
ME3738によるアセトアミノフェン肝傷害時のNrf2防御機能の亢進

川村祐司, 川村祐司, 平塚一幸, 蓮沼惠子, 伊藤富美, 庄司陽子, 今井聖子, 黒沢亨, 田口恵子, 田口恵子, 田口恵子, 芦野隆, 山本雅之, 山本雅之, 山本雅之, 吉田武美

Journal of Toxicological Sciences　32　(Supplement)　2007

ISSN： 0388-1350
Inhibition of endothelial nitric oxide synthase activity and suppression of endothelium-dependent vasorelaxation by 1,2-naphthoquinone, a component of diesel exhaust particles (vol 80, pg 632, 2006)

Yang Sun, Keiko Taguchi, Daigo Sumi, Shigeru Yamano, Yoshito Kumagai

ARCHIVES OF TOXICOLOGY　80　(9)　632-632　2006/09

DOI： 10.1007/s00204-006-0127-8 　

ISSN： 0340-5761
ウルソデオキシコール酸(UDCA)は転写因子Nrf2を活性化し,肝細胞の輸送,解毒代謝,抗酸化ストレス応答を賦活する

岡田浩介, 正田純一, 兵頭一之介, 田口恵子, 山本雅之, 蕨栄治, 石井哲郎, 宇都宮洋才, 小田高司, 後藤信冶

胆汁酸研究会プログラム・抄録集　28th　2006
生体内活性酸素種が引き起こす酸化ストレス-レドックスシグナルの役割-酸化ストレスを生じる大気中微小粒子成分

田口恵子, 熊谷嘉人

日本薬学会年会要旨集　126th　(1)　2006

ISSN： 0918-9823
酸化ストレスを誘発する9,10-フェナントラキノンの解毒排せつ機構

田口恵子, 嶋田恩美, 山野茂, 西山貴仁, 平塚明, 角大悟, 熊谷嘉人

日本薬学会年会要旨集　126th　(3)　2006

ISSN： 0918-9823
ディーゼル排ガス微粒子に含まれる9,10-PhenanthrenequinoneによるDNA鎖切断

柴田三恵, 喜多秀樹, 坂上歩美, 田口恵子, 熊谷嘉人, 山野茂

日本薬学会年会要旨集　125th　(3)　2005

ISSN： 0918-9823
酸化ストレスを生じる大気中微小粒子成分のERKリン酸化

CHANG Pii, 岩本典子, 田口恵子, 角大悟, 山野茂, 熊谷嘉人, 熊谷嘉人

衛生薬学・環境トキシコロジー講演要旨集　2005　2005

ISSN： 0919-2115
大気中微小粒子成分によるタンパク質酸化修飾およびアポトーシスにおけるチオレドキシンの役割

田口恵子, 喜多秀樹, 中村肇, 淀井淳司, 山野茂, 熊谷嘉人

日本薬学会年会要旨集　125th　(3)　2005

ISSN： 0918-9823
酸化ストレスを生じる大気中微小粒子成分はUGTにより無毒化されて細胞外に排泄される

嶋田恩美, 田口恵子, 深見郁夫, 角大悟, 西山貴仁, 平塚明, 山野茂, 熊谷嘉人, 熊谷嘉人

衛生薬学・環境トキシコロジー講演要旨集　2005　2005

ISSN： 0919-2115
ディーゼル排ガスにアレルギーを起こす人はGST欠損/変異か？ (日本薬学会『ファルマシア』)

田口恵子

日本薬学会『ファルマシア』　40　(9)　861-862　2004/09
Publisher: 公益社団法人日本薬学会
ISSN： 0014-8601
Is the human who causes the allergy due to the diesel exhaust particulate the GST deficiency/mutation?

田口恵子

ファルマシア　40　(9)　2004

ISSN： 0014-8601
ディーゼル排ガス微粒子に含まれる9,10-PhenanthrenequinoneのHepG2細胞に対するApoptosis誘導

喜多秀樹, 柴田三恵, 坂上歩美, 田口恵子, 熊谷嘉人, 山野茂

衛生薬学・環境トキシコロジー講演要旨集　2004　2004

ISSN： 0919-2115
大気中微小粒子成分の酸化ストレスと細胞外排せつに係る反応系

藤井佐弥子, 田口恵子, 杉本里香, 石井哲郎, 山野茂, 熊谷嘉人

衛生薬学・環境トキシコロジー講演要旨集　2004　2004

ISSN： 0919-2115
血管内皮細胞における無機ヒ素の活性代謝物モノメチル3価ヒ素のeNOS活性低下とeNOSリン酸化

LI B, SUN Y, 田口恵子, 熊谷嘉人

衛生薬学・環境トキシコロジー講演要旨集　2004　2004

ISSN： 0919-2115
大気中微小粒子成分のシグナル伝達撹乱を介した気道収縮

岩本典子, 菊野庄太, 田口恵子, 山野茂, 熊谷嘉人

衛生薬学・環境トキシコロジー講演要旨集　2004　2004

ISSN： 0919-2115
大気中微小粒子成分9,10-フェナントラキノンによる酸化ストレスとチオレドキシン機能障害

田口恵子, 久森美和, 日吉孝子, 中村肇, 淀井淳司, 石井哲郎, 熊谷嘉人

日本衛生学雑誌　59　(2)　2004

ISSN： 0021-5082
チオレドキシン高発現は大気中微小粒子成分によって生じる酸化ストレスとアポトーシスを抑制する

田口恵子, 中村肇, 淀井淳司, 山野茂, 熊谷嘉人

衛生薬学・環境トキシコロジー講演要旨集　2004　2004

ISSN： 0919-2115
喫煙によりガンを誘発する活性酸素種 (日本化学会『化学と工業』)

田口恵子

日本化学会『化学と工業』　56　(4)　489-489　2003/04

ISSN： 0022-7684
大気中微小粒子成分である9,10-フェナントラキノンとGlyceraldehyde 3-phosphate dehydrogenaseの相互作用

田口恵子, RODRIGUEZ C E, 熊谷嘉人, FROINES J R, CHO A K

衛生薬学・環境トキシコロジー講演要旨集　2003　2003

ISSN： 0919-2115
1,2-ナフトキノンはVR1を介してモルモット気管収縮を生じる大気中微小粒子成分である

菊野庄太, 田口恵子, 石井哲郎, 熊谷嘉人

衛生薬学・環境トキシコロジー講演要旨集　2003　2003

ISSN： 0919-2115
5価無機ヒ素の活性代謝物モノメチル3価ヒ素による血管内皮型NOSの活性低下とcGMP産生系の変動

SUN Y, 田口恵子, PI J, 石井哲郎, 熊谷嘉人

衛生薬学・環境トキシコロジー講演要旨集　2003　2003

ISSN： 0919-2115
大気中微小粒子成分1,2-ナフトキノンは気管収縮を引き起こす

菊野庄太, 田口恵子, 下条信弘, 熊谷嘉人

日本衛生学雑誌　58　(1)　2003

ISSN： 0021-5082
大気中微小粒子成分9,10-フェナントラキノンはスーパーオキサイド依存性の血管収縮を引き起こす

田口恵子, 孫洋, 下条信弘, 熊谷嘉人

日本衛生学雑誌　58　(1)　2003

ISSN： 0021-5082
大気中微小粒子成分1,2-ナフトキノンと共有結合する呼吸器系タンパク質の探索

稲葉貴子, 菊野庄太, 田口恵子, 石井哲郎, 熊谷嘉人

衛生薬学・環境トキシコロジー講演要旨集　2003　2003

ISSN： 0919-2115
大気中微小粒子成分1,2-ナフトキノンによるモルモット気管収縮におけるカプサイシンレセプターの役割

菊野庄太, 田口恵子, 石井哲郎, 熊谷嘉人

大気環境学会年会講演要旨集　44th　2003
ディーゼル排出微粒子に含まれるキノン系化合物による血管収縮作用とそれに関わるメカニズム

田口恵子, 熊谷嘉人, SUN Y, 小出幸絵, 堀口聡美, CHO A K, FROINES J R, 下条信弘

衛生薬学・環境トキシコロジー講演要旨集　2002　2002

ISSN： 0919-2115
NO依存性血管調節系を撹乱するDEP成分フェナントラキノンの体外排せつにおけるNQO1の役割

田口恵子, 熊谷嘉人, 小泉利恵, 石井哲郎, 下条信弘

日本衛生学雑誌　57　(1)　2002

ISSN： 0021-5082
ディーゼル排出微粒子成分1,2-ナフトキノンによる常在型NO合成酵素活性の阻害と内皮依存性血管弛緩の抑制

SUN Y, 熊谷嘉人, 田口恵子, 菊島真, CHO A K, FROINES J R, 下条信弘

衛生薬学・環境トキシコロジー講演要旨集　2002　2002

ISSN： 0919-2115
ディーゼル排出微粒子成分フェナントラキノンと生体内抗酸化物ジヒドロリポ酸の相互作用によるCu,Zn-SODの機能障害

小泉利恵, 田口恵子, 杉本里香, 下条信弘, 熊谷嘉人

衛生薬学・環境トキシコロジー講演要旨集　2002　2002

ISSN： 0919-2115
ディーゼル排出微粒子(DEP)に含まれるキノン類のチオレドキシン(TRX)/チオレドキシン還元酵素(TR)系に対する影響

喜多秀樹, 田口恵子, 熊谷嘉人, 山野茂

日本薬学会年会要旨集　122nd　(3)　2002

ISSN： 0918-9823
Oxidative modification of protein sulfhydryl groups by phenanthraquinone, a component of diesel exhaust particles (1) : The inhibition mechanism of eNOS activity

KUMAGAI Yoshito

56　(1)　255-255　2001/04/01

ISSN： 0021-5082
Oxidative modification of protein sulfhydryl groups by phenanthraquinone, a component of diesel exhaust particles (2): examination using rat pulmonary organ and participation of reactive oxygen species

TAGUCHI Keiko

56　(1)　256-256　2001/04/01

ISSN： 0021-5082
Enzyme Responsible for Detoxification of a Component of Diesel Exhaust Particles, Phenanthraquinone that Disrupts NO-Dependent Vascular Tone.

田口恵子, 熊谷嘉人, 小泉利恵, 石井祐次, 石井哲郎, CHO A K, 下条信弘

フォーラム2001:衛生薬学・環境トキシコロジー講演要旨集平成13年　2001
Decreased the Hepatic Thioredoxin Reductase and Protein Sulhydryl Contentby Inner Mongolia-Type Chronic Arsenic Exposure.

二階堂正聡, PI J, 熊谷嘉人, 田口恵子, 堀口聡美, 石井祐次, SUN G, 下条信弘

フォーラム2001:衛生薬学・環境トキシコロジー講演要旨集平成13年　2001
ディーゼル排出微粒子に含まれるフェナントラキノンの細胞毒性酸化ストレス防御系タンパク質の特異的分解

石井哲郎, 田口恵子, 菊島真, 下条信弘, 熊谷嘉人

生化学　73　(8)　2001

ISSN： 0037-1017
ディーゼル排出微粒子成分であるフェナントラキノンのタンパク質性SH基の酸化修飾

小出幸枝, 熊谷嘉人, 田口恵子, 下条信弘

環境トキシコロジーシンポジウム講演要旨集　2000　2000

ISSN： 0919-2115

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Books and Other Publications 6

酸化ストレスの医学改訂第２版

吉川敏一監修, 内藤裕二, 豊國伸哉編集

診断と治療社　2014/09
毒性の科学：分子・細胞から人間集団まで

熊谷嘉人, 姫野誠一郎, 渡辺知保, d, 田口恵子

東京大学出版会　2014/02
Protein modifications in pathogenic dysregulation of signaling

Jun-ichiro Inoue, Mutsuhiro Takekawa

Springer　2014
実験医学増刊号

山本雅之, 赤池孝章, 一條秀憲, 森泰生 ed, 田口恵子, 本橋ほづみ

羊土社　2012/11/01
実験医学増刊号

井上純一郎, 武川睦寛, 徳永文稔, 今井浩三, 田口恵子, 山本雅之

羊土社　2012/03/25
日本薬学会環境・衛生部会トピックス

田口恵子

日本薬学会環境・衛生部会　2010/09

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Presentations 105

Pathophysiological Analyses in the Liver of KEAP1 knockout rats

2024/11/07
Pathophysiological Analyses in the Liver of KEAP1 knockout rats

2024/11/06
KEAP1-NRF2システムにおける付加体形成

田口恵子

第51回日本毒性学会学術年会　2024/07/05
NRF2活性化がん：古き実験動物モデルから診断と治療に向けて Invited

田口恵子

第50回日本毒性学会学術年会　2024/06/20
Metabolic Reprogramming in Nrf2-driven Proliferation of Normal Rat Hepatocytes by Lead Nitrate

Keiko Taguchi, Marta Anna Kowalik, Marina Serra, Andrea Caddeo, Elisabetta Puliga, Marina Bacci, Seizo Koshiba, Jin Inoue, Eiji Hishinuma, Andrea Morandi, Silvia Giordano, Andrea Perra, Masayuki Yamamoto, Amedeo Columbano

The Environmental Response VI　2023/11
NRF2-activated Cancers and Toxicology Invited

Keiko Taguchi, Masayuki Yamamoto

The 10th International Congress of Asian Society of Toxicology (ASIATOX-X)　2023/07
Woman Toxicologists in Japan. Symposium Invited

Keiko Taguchi

The 10th International Congress of Asian Society of Toxicology (ASIATOX-X)　2023/07
NRF2 activation status determines cell competition in the esophagus Invited

Keiko Taguchi, Wataru Hirose, Masayuki Yamamoto

Society of Toxicology (SOT) 62nd annual meeting and ToxExpo　2023/03/21
Protective effects of Nrf2 against radiation-induced oral mucositis

Keiko Taguchi, Shun Wakamori, Masayuki Yamamoto

The 3rd STINT-JSPS symposium. Karolinska Institute　2023/01
Fate of Nrf2-activated cells in tissue homeostasis

Keiko Taguchi, Wataru Hirose, Masayuki Yamamoto

XVIth International Congress of Toxicology 2022 (ICT2022)　2022/09/20
ラットモデルから紐解くKeap1-Nrf2システムの新たな役割 Invited

田口恵子, 山本雅之

先端モデル動物支援プラットフォーム2020年度成果発表会　2021/02/02
肝毒性とKeap1-Nrf2システム

田口恵子, 山本雅之

第47回日本毒性学会学術年会　2020/07/01
Constitutive Nrf2 activation in Keap1 knockout rats causes jaundice and polyurea

Keiko Taguchi, Nanae Osanai, Yuri Satoh, Tomoji Mashimo, Masayuki Yamamoto

The Environmental Response V/ 17th JBS Biofrontier Symposium　2019/09
Unveiling new roles of Keap1-Nrf2 System by using rat models

Keiko Taguchi, Masayuki Yamamoto

The Environmental Response V/ 17th JBS Biofrontier Symposium　2019/09/13
Keap1欠失ラットはNrf2に依存して重篤な肝障害を引き起こす

田口恵子, 小山内七重, 佐藤由莉, 真下知士, 山本雅之

第46回日本毒性学会学術年会　2019/06/27
Aflatoxin B1 induces fibrosis and cirrhosis in Nrf2 knockout rats

Keiko Taguchi, Nanae Osanai, Eriko Naganuma, Thomas W. Kensler, Masayuki Yamamoto

58th Annual Meeting of Society of Toxicology (SOT)　2019/03
Nrf2 activation acquired in a transition from steatosis to liver cancer. Invited

Keiko Taguchi, Risa Ichinohe, Masayuki Yamamoto

2017 International Congress Obesity and Metabolic Syndrome (ICOMES2017)　2017/09/02
Pten欠失肝臓がんにおけるNrf2活性獲得の意義 Invited

田口恵子, 一戸理沙, 山本雅之

第5回がんと代謝研究会　2017/07/13
毒性学における転写因子Nrf2の貢献 Invited

田口恵子

第44回日本毒性学会学術年会　2017/07/11
オートファジーとKeap1-Nrf2システム

田口恵子

第44回日本毒性学会学術年会　2017/07/12
The Nrf2 knockout rat as a toxicological tool

Keiko Taguchi, Misaki Takaku, Patricia A. Egner, Thomas W. Kensler, Masayuki Yamamoto

56th Annual Meeting and ToxExpo (SOT; Society of Toxicology)　2017/03
毒性学におけるNrf2欠失ラットの貢献 Invited

田口恵子, 山本雅之

第10回ラットリソースリサーチ研究会　2017/02/03
オートファジー破綻がもたらす病態のNrf2を標的とした治療戦略

田口恵子, 鈴木隆史, 山本雅之

第10回オートファジー研究会　2016/11
Nrf2 is a critical factor for hepatocellular adenoma in impaired autophagy

Keiko Taguchi, Masaaki Komatsu, Masayuki Yamamoto

41st NAITO Conference: Cancer Heterogeneity and Plasticity: Relevance to Therapeutic Resistance　2016/07
Nrf2の恒常的活性化はヘム合成阻害剤による肝毒性を軽減する

田口恵子, 増井紗帆, 山本雅之

第43回日本毒性学会学術年会　2016
Nrf2 is a critical factor for hepatocellular adenoma in impaired autophagy

Keiko Taguchi, Masaaki Komatsu, Masayuki Yamamoto

Tenth AACR-JCA Joint Conference on Breakthroughs in Cancer Research: From Biology to Therapeutics　2016/02
Nrf2はPten欠失による脂肪肝炎から肝臓がんの移行を促進する

田口恵子, 一戸理沙, 山本雅之

第88回日本生化学会/第38回日本分子生物学会合同大会　2015/12/04
2つのタンパク質分解系による統合的なNrf2の制御メカニズム Invited

田口恵子

第88回日本生化学会大会　2015/12/03
Nrf2欠失ラットはアフラトキシンB1による肝毒性に対して脆弱である

田口恵子, 高久美咲, Thomas W. Kensler, 山本雅之

第42回日本毒性学会学術年会　2015/06/30
A new tool for toxicology: Nrf2 knockout rat Invited

Keiko Taguchi, Misaki Takaku, Masayuki Yamamoto

The 7th International Congress of Asian Society of Toxicology (ASIATOX-VII)　2015/06/25
Nrf2 knockout rat is sensitive to aflatoxin B1 hepatotoxicity

Keiko Taguchi, Misaki Takaku, Patricia A. Egner, Thomas W. Kensler, Masayuki Yamamoto

University of Pittsburgh Cancer Institute (UPCI) Scientific Retreat　2015/06
Mechanisms for Nrf2 regulation by the protein degradation

2015/03/27
Establishment and characterization of Nrf2 knockout rats

Keiko Taguchi, Misaki Takaku, Masanobu Morita, Masayuki Yamamoto

2015/01/08
Nrf2の活性制御破綻がもたらす肝病態

第87回日本生化学会大会　2014/10/15

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1S02p: 難治疾患を治療する創薬・医療イノベーション：基礎研究から新薬の開発・上市まで
Liver diseases caused by perturbation of Nrf2 regulation International-presentation

Keiko Taguchi, Hozumi Motohashi, Masayuki Yamamoto

第73回日本癌学会学術総会　2014/09/25

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07. シグナル伝達破綻による発がんスパイラルの加速
Two-step regulation of Nrf2 activity in the liver International-presentation

Keiko Taguchi, Hozumi Motohashi, Masayuki Yamamoto

フォーラム2014衛生薬学・環境トキシコロジー　2014/09/19

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Japan/Korea Joint Symposium on Pharmaceutical Health Science and Environmental Toxicology, 日韓次世代シンポジウム
転写因子Nrf2の活性制御メカニズムと病態

田口恵子, 本橋ほづみ, 山本雅之

転写若手放射線生物学研究会勉強会　2014/08/10
Molecular Mechanisms and Functions of Keap1-Nrf2 system International-presentation

Keiko Taguchi, Hozumi Motohashi, Masayuki Yamamoto

2014 International Symposium and Annual Meeting of the KSABC (The Korean Society for Applied Biological Chemistry)　2014/06/20
Molecular Mechanisms and Functions of Keap1-Nrf2 system International-presentation

Keiko Taguchi, Hozumi Motohashi, Masayuki Yamamoto

Gyeonggi Institute of Science & Technology Promotion　2014/06/19
肝毒性物質に応答した肝保護にはたらくNrf2の役割

田口恵子, 本橋ほづみ, 山本雅之

日本生化学会東北支部第80回例会・シンポジウム　2014/05/10
Nrf2 enhances cholangiocyte expansion in Pten-deficient livers International-presentation

Keiko Taguchi, Hozumi Motohashi, Masayuki Yamamoto

The Environmental Response IV　2014/02/28
PtenとKeap1-Nrf2システムの破綻が引き起こす肝病態の解析

田口恵子, 本橋ほづみ, 鈴木聡, 山本雅之

平成25年度個体レベルでのがん研究支援活動ワークショップ　2014/02/17
Nrf2は門脈枝結紮による代償的肝肥大を促進する

田口恵子, 白崎圭一, 本橋ほづみ, 山本雅之

新学術領域研究「修飾シグナル病」領域推進会議　2014/01/25
転写因子Nrf2はPten欠損肝臓において胆管増生を促進する

田口恵子, 山本雅之, 本橋ほづみ

加齢医学研究所第141回集談会　2014/01/17
門脈枝結紮による代償的肝肥大におけるNrf2の役割

田口恵子, 白崎圭一, 本橋ほづみ, 山本雅之

新学術研究「修飾シグナル病」若手ワークショップ　2013/10/21
肝毒性物質による肝肥大における転写因子Nrf2の役割

田口恵子, 本橋ほづみ, 伊藤暢, 田中稔, 宮島篤, 山本雅之

フォーラム2013：衛生薬学・環境トキシコロジー　2013/09/11
肝毒性物質による肝肥大におけるNrf2の貢献

田口恵子, 本橋ほづみ, 伊藤暢, 田中稔, 宮島篤, 山本雅之

第86回日本生化学会　2013/09/11
酸化ストレス応答機構Keap1-Nrf2システムと肝病態

平成25年度日本薬学会東北支部第12回生物化学若手研究者セミナー『酸化ストレスに応答機構研究の展開』　2013/09/07
転写因子Nrf2の制御破綻が引き起こす肝病態

平成25年度「がん研究分野の特性等を踏まえた支援活動」公開シンポジウム　2013/08/22
肝疾患におけるNrf2の機能解析

第6回レドックス・ライフイノベーション第170委員会　2013/08/22
肝疾患における転写因子Nrf2の機能変化

新学術領域研究「修飾シグナル病」領域推進会議　2013/07/05
肝毒性物質による肝肥大におけるNrf2の貢献

田口恵子, 本橋ほづみ, 山本雅之

新学術領域研究「修飾シグナル病」領域推進会議　2013/07/05
Nrf2 enhances a hepatotoxin-induced hepatic cell expansion International-presentation

Keiko Taguchi, Hozumi Motohashi, Masayuki Yamamoto

The XIII International Congress of Toxicology (ICT2013)　2013/06/30
オートファジーによるKeap1タンパク質分解とレドックス恒常性維持

田口恵子, 藤川奈々子, 本橋ほづみ, 山本雅之

GCOEシンポジウム～Network Medicineによる医学・生命科学の新たな潮流～　2013/02/01
Reciprocal activation between Nrf2 and a proliferative signaling in liver International-presentation

Keiko Taguchi, Hozumi Motohashi, Masayuki Yamamoto

1st International Symposium on Protein Modifications in Pathogenic Dysregulation of Signaling　2013/02/01
Reciprocal activation between Nrf2 and a proliferative signaling in liver International-presentation

Keiko Taguchi, Hozumi Motohashi, Masayuki Yamamoto

Kumamoto University Core Research Project B “Center for Frontier Research on Life Style an Stress Signal” and Grants-in-Aid for Scientific Research on Innovative Areas (Research in a Proposed Research Area), MEXT, Japan “Signaling Functions of Reactive Ox　2012/12/18
肝臓における２つのNrf2活性制御機構と胆管形成

田口恵子, 本橋ほづみ, 山本雅之

第85回日本生化学会　2012/12/14
肝臓における２つのNrf2活性制御機構と胆管形成

田口恵子, 本橋ほづみ, 山本雅之

第85回日本生化学会　2012/12/14
肝臓における２つのNrf2活性制御機構と胆管形成

田口恵子, 本橋ほづみ, 山本雅之

フォーラム2012:衛生薬学・環境トキシコロジー　2012/10/25
PI3K経路により変化する転写因子Nrf2の機能

がん・エピゲノム研究会　2012/10/24
レドックス恒常性維持に重要なオートファジーによるKeap1タンパク質の分解

田口恵子, 藤川奈々子, 本橋ほづみ, 山本雅之

2012年度新学術領域研究「修飾シグナル病」若手ワークショップ　2012/10/03
Keap1-Nrf2 system for maintenance of redox homeostasis International-presentation

Keiko TAGUCHI, Nanako FUJIKAWA, Hozumi MOTOHASHI, Masayuki YAMAMOTO

The 6th International Congress of Asian Society of Toxicology (ASIATOX-VI)　2012/07/17
Keap1-Nrf2システムとPI3K-Akt経路のクロストークと肝病態

2012年度新学術領域「転写代謝システム」班会議　2012/07/02
Crosstalk between Keap1-Nrf2 system and Pten-PI3K-Akt signaling regulates cellular proliferation and differentiation International-presentation

Keiko Taguchi, Hozumi Motohashi, Yamamoto M

The 33rd NAITO Conference “Oxygen Biology: Hypoxia, Oxidative Stress and Diseases”　2012/06/26
Keap1 Degradation by Autophagy for the Maintenance of Redox Homeostasis International-presentation

Taguchi K, Fujikawa N, Motohashi H, Yamamoto M

UK-Japan Research Exchange Symposium Molecular Mechanisms of Stress Response in Disease　2012/04/06
THE NRF2-KEAP1 STRESS RESPONSE PATHWAY: MOLECULAR BASIS OF ADAPTIVE RESPONSES AND PATHOGENESIS International-presentation

Masayuki Yamamoto, Hirofumi Kurokawa, Takafumi Suzuki, Keiko Taguchi, Hozumi Motohashi

Society of Toxicology　2012/03/06
Keap1-Nrf2システムとPten-PI3K-Aktシグナルのクロストークは肝臓における細胞増殖と分化を制御する

田口恵子, 本橋ほづみ, 山本雅之

GCOE冬の合宿2012　2012/02/04
転写因子Nrf2の活性制御タンパク質Keap1の分解と合成

田口恵子, 藤川奈々子, 本橋ほづみ, 山本雅之

フォーラム2011：衛生薬学・環境トキシコロジー　2011/10/27
Keap1 degradation by autophagy for the maintenance of redox homeostasis International-presentation

Nanako Fujikawa, Keiko Taguchi, Hozumi Motohashi, Masayuki Yamamoto

16th World Congress on Advances in Oncology and 14th International Symposium on Molecular Medicine　2011/10/06
レドックス恒常性維持に重要なKeap1分解機構の解明

藤川奈々子, 田口恵子, 本橋ほづみ, 山本雅之

平成23年度がん若手ワークショップ　2011/08/31
Keap1-Nrf2システムとAktシグナルの相互作用と肝疾患

田口恵子, 本橋ほづみ, 山本雅之

新学術領域研究「修飾シグナル病」領域推進会議　2011/07/01
レドックス恒常性維持におけるオートファジーによるKeap1の分解

藤川奈々子, 田口恵子, 本橋ほづみ, 山本雅之

新学術領域研究「活性酸素シグナル」領域推進会議　2011/05/14
THE NRF2-KEAP1 STRESS RESPONSE PATHWAY: MOLECULAR BASIS OF ADAPTIVE RESPONSES AND PATHOGENESIS International-presentation

Masayuki Yamamoto, Hirofumi Kurokawa, Takafumi Suzuki, Keiko Taguchi, Hozumi Motohashi

Anniversary & Annual meeting & ToxExpo 2011　2011/03/06
Co-activation of Nrf2 and Akt causes bile ductal metaplasia International-presentation

Keiko Taguchi, Hozumi Motohashi, Masayuki Yamamoto

Tohoku University Global COE for conquest of Signal Transduction Diseases with “Network Medicine”, Network Medicine Winter Camp of GCOE; The Cultivation for New Generation of Scientists-　2011/02/05
Nrf2-Keap1生体防御システムの機能とその破綻による病態の解明

平成22年度東北大学医学部奨学賞（銀賞）　2011/01/14
上皮細胞における転写因子Nrf2の活性化

田口恵子, 鈴木隆史, 本橋ほづみ, 山本雅之

フォーラム2010：衛生薬学・環境トキシコロジー　2010/09/09
上皮細胞における転写因子Nrf2の活性化

田口恵子, 鈴木隆史, 本橋ほづみ, 山本雅之

第76回日本生化学会東北支部会例会　2010/05/08
Cell type-specific Nrf2 activation: different feature in hepatocytes and epithelial cells International-presentation

Keiko Taguchi, Masayuki Yamamoto

堀場国際会議／疾患生命工学センターシンポジウム　2009/10/26
Nrf2は肺における新規転移抑制因子として働く

佐藤大希, 田口恵子, 森口尚, 鈴木隆史, 海老名雅仁, 貫和敏博, 山本雅之

日本癌学会　2009/10/01
オートファジー機能不全によるNrf2活性化

田口恵子, 小松雅明, 田中啓二, 山本雅之

G-COE冬の合宿　2009/02/14
Nrf2 activation and hepatomegaly in autophagy International-presentation

Keiko Taguchi, Masaaki Komatsu, Keiji Tanaka, Masayuki Yamamoto

Molecular Mechanism of Environmental Response to Food and Oxygen III　2009/02/09
Urethane-induced lung carcinogenesis in Nrf2 knockout mice International-presentation

Hironori Satoh, Keiko Taguchi, Takashi Moriguchi, Masahito Ebina, Toshihiro Nukiwa, Masayuki Yamamoto

Molecular Mechanism of Environmental Response to Food and Oxygen III　2009/02/09
分子毒性学における転写因子研究：Nrf2活性化が生体に及ぼす正負の作用

田口恵子

第31回日本分子生物学会年会・第81回日本生化学会大会合同大会　2008/12/09
酸化ストレスを生じるディーゼル排出微粒子成分の毒性発現と生体防御機構の解明

田口恵子

フォーラム2008：衛生薬学・環境トキシコロジー　2008/10/17
Morphological changes during constitutive Nrf2 activation in vivo

田口恵子, Jonathan, M. Mahe, 川谷幸恵, 鈴木隆史, 山本雅之

がん特定領域研究若手ワークショップ　2008/09/03
Phenotypic analyses of constitutive Nrf2 activation by partially disruption of Keap1.

Taguchi K, Pfeiffer MY, Maher JM, Kawatani Y, Suzuki T, Yamamoto M

Environmental Response Project International Symposium on “The Enviromental Response”　2007/12/21
Keap1遺伝子部分破壊によるNrf２抑制破綻の表現型解析

田口恵子, Martin J, Pfeiffer, Jonathan M. Maher, 川谷幸恵, 鈴木隆史, 山本雅之

フォーラム2007：衛生薬学・環境トキシコロジー　2007/11/01
恒常的なNrf2活性化によるアセトアミノフェン毒性発現の防御

田口恵子, Jonathan, M. Maher, 川谷幸恵, 鈴木隆史, 山本雅之

第34回日本トキシコロジー学会　2007/06/27
シンポジウム「生体内活性酸素種が引き起こす酸化ストレス？レドックスシグナルの役割？」

田口恵子, 熊谷嘉人

第126年会日本薬学会　2006/03/28
Glucuronidation as a metabolic pathway terminating redox cycling of 9,10-phenanthraquinone associated with oxidative stress International-presentation

Keiko Taguchi, Yoshito Kumagai

Society of Toxicology　2006/03/05
Two-electron reduction of 9,10-phenanthraquinone associated with redox cycling-dependent oxidative stress International-presentation

Keiko Taguchi, Yoshito Kumagai

International Redox Network 2005　2005/11/13
大気中微小粒子成分によるタンパク質酸化修飾およびアポトーシスにおけるチオレドキシンの役割

田口恵子, 喜多秀樹, 中村肇, 淀井淳司, 山野茂, 熊谷嘉人

第125年会日本薬学会　2005/03/29
大気中微小粒子成分によるタンパク質酸化修飾およびアポトーシスにおけるチオレドキシンの役割

田口恵子, 喜多秀樹, 中村肇, 淀井淳司, 山野茂, 熊谷嘉人

第125年会日本薬学会　2005/03/29
Two-electron reduction of 9,10-phenanthraquinone associating with redox cycling-dependent oxidative stress International-presentation

Keiko Taguchi, Sayako Fujii, Shigeru Yamano, Arthur K. Cho, Yoshito Kumagai

JST-ERATO Yamamoto Environmental Response Project International Symposium: Molecular Mechanism of Environmental Response to Food and Oxygen　2005/03/13
大気中微小粒子成分によるタンパク質の酸化傷害およびアポトーシス誘導におけるチオレドキシンの役割

第４回分子予防医学研究会　2004/12
チオレドキシン高発現は大気中微小粒子成分によって生じる酸化ストレスとアポトーシスを抑制する

田口恵子, 中村肇, 淀井淳司, 山野茂, 熊谷嘉人

フォーラム2004:衛生薬学・環境トキシコロジー　2004/10/25
大気中微小粒子成分9,10-フェナントラキノンによる酸化ストレスとチオレドキシン機能障害

田口恵子, 久森美和, 日吉孝子, 中村肇, 淀井淳司, 石井哲郎, 熊谷嘉人

第74回日本衛生学会　2004/03/13
大気中微小粒子成分9,10-フェナントラキノンによる酸化ストレスとチオレドキシン機能障害

田口恵子, 久森美和, 日吉孝子, 中村肇, 淀井淳司, 石井哲郎, 熊谷嘉人

「環境応答の分子機構の解明」研究総括シンポジウム　2004/01/13
大気中微小粒子成分1,2-ナフトキノンによるEGFR自己リン酸化/VR1を介した気管収縮

田口恵子, 菊野庄太, 石井哲郎, 熊谷嘉人

第３回分子予防医学研究会　2003/12/19
大気中微小粒子成分である9,10-フェナントラキノンとGlyceraldehyde 3-phosphate dehydrogenaseの相互作用

田口恵子, Chester E. Rodriguez, 熊谷嘉人, John, R. Froines, Arthur K. Cho

フォーラム2003：衛生薬学・環境トキシコロジー　2003/10/23
大気中微小粒子成分9,10-フェナントラキノンはスーパーオキサイド依存性の血管収縮を引き起こす

田口恵子, 孫洋, 下條信弘, 熊谷嘉人

第73回日本衛生学会　2003/03/13
ディーゼル排出微粒子に含まれるキノン系化合物による血管収縮作用とそれに関わるメカニズム

田口恵子, 熊谷嘉人, 孫洋, 小出幸絵, 堀口聡美, Arthur K. Cho, John, R. Froines, 下條信弘

フォーラム2002：衛生薬学・環境トキシコロジー　2002/10/24
NO依存性血管調節系を撹乱するDEP成分フェナントラキノンの体外排泄におけるNQO1の役割

田口恵子, 熊谷嘉人, 小泉利恵, 石井哲郎, 下條信弘

第72回日本衛生学会　2002/03/13
NO依存性血管調節系を撹乱するディーゼル排出微粒子成分フェナントラキノンの体外排泄に関与する酵素

田口恵子, 熊谷嘉人, 小泉利恵, 石井祐次, 石井哲郎, Arthur K. Cho, 下條信弘

フォーラム2001：衛生薬学・環境トキシコロジー　2001/10/30
ディーゼル排出微粒子成分であるフェナントラキノンのタンパク性SH基の酸化修飾（その２）：ラット肺組織を用いた検討と活性酸素種の関与

田口恵子, 熊谷嘉人, 小出幸絵, 下條信弘

第71回日本衛生学会　2001/04/13

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Research Projects 16

Deciphering the mechanisms of pancreatic cancer intractability via sulfur biology and its therapeutic application

Masamune Atsushi

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (B)

Institution: Tohoku University

2022/04/01 - 2025/03/31

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This study aimed to elucidate the importance of reactive sulfur species in the adaptation of pancreatic cancer to severe microenvironment. We introduced heterozygous knockout of Cars2 into the pancreatic cancer mouse model, KPC mouse. Formation of precancerous lesions in these mice tended to decrease. In pancreatic stellate cells with Cars2 heterozygous knockout, the growth promoting effect on pancreatic cancer cells attenuated, with reduction in intracellular persulfides. Furthermore, high expression of enzymes that regulated by the oxidative stress response pathway was found to be a poor prognostic factor in pancreatic cancer patients. Knockdown of this enzyme suppressed the proliferation of the human pancreatic cancer cell line and induced cell cycle inhibitory factors.
肝臓の組織構築におけるNrf2の新たな機能

田口恵子

Offer Organization: 日本学術振興会

System: 科学研究費助成事業

Category: 基盤研究(C)

Institution: 東北大学

2022/04/01 - 2025/03/31

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Keap1-Nrf2システムは、酸化ストレスや毒物により活性化して、抗酸化酵素や解毒代謝酵素をコードする遺伝子の発現を亢進する生体防御機構である。Keap1やNrf2の遺伝子変異によってNrf2の活性制御メカニズムが破綻したがん細胞は、過剰にNrf2が活性化して細胞増殖を促進することが報告されている。それ故に、新たに遺伝子改変ラットを用いて、Nrf2の異常な活性化が引き起こす生体反応を明らかににすることを目的とした。・ Keap1欠失ラットにおけるNrf2活性化と肝臓の組織構築野生型（K2）、Keap1ヘテロ欠失（K1）およびKeap1欠失（K0）ラットを作出した。K0ラットは生後０日齢で死亡し、肝臓の表現型が顕在化した。これには、肝臓の発生過程におけるNrf2の過剰な活性化が影響したと考えられた。そこで、Keap1欠失によるNrf2依存性を調べるため、さらに、Keap1::Nrf2ヘテロ欠失（K0N1）とKeap1::Nrf2二重欠失（K0N0）ラットを作出した。K0N1ラットでは生後致死が半数程度回避でき、K0N0ラットはK2ラットと同様に正常に生育した。0日齢の5つの遺伝子型ラットを用いて、血液生化学検査を行ったところ、K0ラットではビリルビンの上昇がみられ、黄疸の症状と一致した。また、ビリルビンの上昇やK0N1およびK0N0ラットでは軽減した。そこで、Nrf2の活性化と代表的なNrf2標的遺伝子の発現を調べ、Nrf2の活性化を検証した。K0ラットではNrf2の核蓄積がみられ、Nrf2標的遺伝子の発現も上昇したが、K0N1および K0N0ラットでは減少した。以上より、Keap1欠失によるNrf2の活性化が致死の原因であり、肝臓に黄疸の症状を呈した。
硫黄生物学から紐解く膵癌難治化機構の解明と治療応用

正宗淳, 赤池孝章, 濱田晋, 田口恵子

Offer Organization: 日本学術振興会

System: 科学研究費助成事業

Category: 基盤研究(B)

Institution: 東北大学

2022/04/01 - 2025/03/31

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本年度は研究初年度として、Cars2ヘテロノックアウト付加KPCマウスの作製を実施した。Cars2ヘテロノックアウトKPCマウス（膵特異的変異Kras, p53発現）、Cars2ヘテロノックアウトKCマウス（膵特異的変異Kras発現）が得られ、野生型KPCマウスと同様に生後90日まで生存することを確認した。Cars2ヘテロノックアウトKCマウス膵組織においては前癌病変であるpancreatic intraepithelial neoplasmの形成数が減少する傾向がみられた。Cars2ヘテロノックアウトKPCマウス1頭で膵発癌がみられたが、組織型は野生型KPCマウスと類似した腺癌を呈していた。Cars2ヘテロノックアウトマウスより膵星細胞を分離し、SV40導入により不死化し細胞株を樹立した。樹立細胞株は10％ウシ胎児血清添加DMEMにて継代可能であったが、野生型膵星細胞株に比べて細胞増殖能・遊走能は低下していた。Cars2ヘテロノックアウト膵星細胞の酸化ストレス耐性を評価するためにマレイン酸ジエチル処理後の細胞生存率を野生型膵星細胞株と比較したが、Nrf2欠損膵星細胞株とは異なり明らかな脆弱性は認めなかった。我々はこれまでにヒトおよびマウス膵星細胞の培養上清刺激が膵癌細胞の増殖を促進することを報告してきたが（Takikawa, Pancreas 2017; Tanaka, AJP-GI 2021）、Cars2ヘテロノックアウト膵星細胞株の培養上清刺激ではむしろ増殖が抑制されることが判明した。処理後のKPCマウス膵癌細胞株では細胞周期の抑制因子であるp21発現が増加し、促進因子のcyclin D1は減少していた。
Deciphering Molecular Basis for the Anti-Oxidative Stress Response and Application of the Basis for Disease Prevention and Therapy

Yamamoto Masayuki

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (S)

Institution: Tohoku University

2019/06/26 - 2024/03/31

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In this study, we aimed to clarify the molecular mechanisms of the oxidative stress response mechanism by the KEAP1-NRF2 system, and to demonstrate the contribution of NRF2 to the prevention and treatment of age-related diseases. We elucidated the mechanism by which KEAP1 selectively uses multiple sensor residues. We also demonstrated that NRF2 activation is effective in preventing and treating diseases such as diabetes and dementia. Furthermore, we succeeded in the first space travel experiment with Nrf2 gene knockout mice, and clarified the contribution of NRF2 to space stress response.
Development of esophagus cancer acquired Nrf2 activation

TAGUCHI Keiko

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (C)

Institution: Tohoku University

2019/04/01 - 2022/03/31

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We examined how Nrf2 plays roles in esophageal cancers developed by a chemical carcinogen, using two model mice that harbor acquired deletion of Nrf2 or Keap1 genes in esophageal epithelium. Partial appearance o Keap1-deleted cells in esophageal epithelium conferred DNA damage to Keap1-expressing cells, resulting in 4NQO-induced tumor promotion. Nrf2-addicted cancers are found approximately 30% of esophageal squamous cell carcinoma. This study is useful to understand development of Nrf2-addicted cancers.
Development of novel therapy for pancreatic cancer based on the regulation of oxidative stress responses

Masamune Atsushi

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (B)

Institution: Tohoku University

2019/04/01 - 2022/03/31

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This research project aimed to develop intervention methods for pancreatic cancer according to the Nrf2 activation status. We identified that halofuginone, the inhibitor of Nrf2, represses Aldh3a1 expression. Halofuginone potentiates the effects of the anticancer agent both in vitro and in vivo. The enhancement of tumorigenicity by pancreatic stellate cells depend on stellate cells' Nrf2. Inhibition of amino acid metabolism was more effective in Nrf2-activated pancreatic cancer cells.
生体の酸化ストレス応答の分子メカニズム解明とその疾病予防・治療への応用

山本雅之, 田口恵子, 鈴木隆史

Offer Organization: 日本学術振興会

System: 科学研究費助成事業

Category: 基盤研究(A)

Institution: 東北大学

2019/04/01 - 2020/03/31

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私たちは常に外界からのストレスに曝されており、それに対する応答は生体の恒常性維持に必須である。酸素、紫外線、大気や食物中の化学物質などが重要な環境由来ストレスとなっているが、これらのストレス因子の増加は生体内レドックスバランスの撹乱を招来し、多くの疾患の共通基盤を形成している。超高齢化社会での健康長寿を実現するためには、生体の酸化ストレス応答機構全容の理解とその制御メカニズムの詳細な解明が極めて重要である。本申請研究では、生体の酸化ストレス応答機構において中心的な役割を果たしている KEAP1-NRF2 制御系の機能メカニズムの解明に挑むとともに、ストレス関連疾患の予防・治療に対する同制御系の貢献を明らかにする。特に、生体が KEAP1 を利用して過剰な酸素によるストレスを感知するメカニズムとそのストレス感知が生体防御遺伝子群の発現の変化を惹起するメカニズムの解明に挑戦する。本申請研究は、NRF2 活性化による疾病予防・治療の有効性やその健康長寿実現への貢献を実証するものと期待される。本年度は、１）KEAP1-NRF2制御系による酸化ストレス感知メカニズムの解析、２）KEAP1-NRF2制御系の構造機能連関解析、３）加齢関連疾患モデル動物を用いたNRF2活性化の有効性検証を行うため、それぞれの解析に必要な実験系のセットアップを主に実施した。
オートファジー破綻がもたらす病態のNrf2を標的とした治療戦略

田口恵子

Offer Organization: 日本学術振興会

System: 科学研究費助成事業

Category: 新学術領域研究(研究領域提案型)

Institution: 東北大学

2016/04/01 - 2018/03/31

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Nrf2は多くの下流遺伝子の発現を制御する転写因子である。Nrf2の活性はユビキチンリガーゼアダプター分子であるKeap1によって負に制御されている。Keap1に結合したNrf2は、ユビキチン化されてタンパク質分解を受ける。タンパク質分解機構のひとつとして、プロテアソームと並んでオートファジーが知られている。我々はこれまでに、Keap1タンパク質がオートファジーによって分解されることを明らかにしている。肝臓においてオートファジーの機能が破綻すると、本来分解されるべきp62タンパク質やユビキチン化タンパク質が異常蓄積する。p62はKeap1とNrf2の結合を妨げるため、オートファジーの機能が破綻した肝臓ではNrf2が活性化する。オートファジーの機能が破綻したマウス肝臓は、肝腫瘍を形成する。この肝腫瘍の形成には、オートファジーの破綻により活性化したNrf2が関与することを示した。Nrf2の活性は主にKeap1によって制御されているが、二次的なNrf2の制御系として、リン酸化されたNrf2がbTrCPによってユビキチン化を受けることが最近報告された。そこで、オートファジーの機能が破綻したマウスの肝臓において、Nrf2のリン酸化に関わるシグナルカスケードとしてAktのリン酸化を調べたところ、オートファジーの破綻によりAktのリン酸化が亢進していることが明らかとなった。よって、オートファジーの機能が破綻した際におこるNrf2の活性化メカニズムとして、p62タンパク質の蓄積に加えて、AktシグナルカスケードによるNrf2リン酸化の抑制によるNrf2タンパク質分解の抑制が考えられた。
Role of oxidative stress response in pancreatic diseases and therapeutic application

Masamune Atsushi

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (B)

Institution: Tohoku University

2015/04/01 - 2018/03/31

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We assessed the effect of continuous Nrf2 activation due to the pancreas-specific deletion of Keap1 in a mouse model of pancreatic cancer. Pancreas-specific expression of mutant Kras and p53 or Kras alone with conditional knockout of Keap1 resulted in poor weight gain after birth, leading to early death due to loss of pancreatic parenchyma. Additional introduction of Nrf2+/- or Nrf2-/- background rescued this phenotype, suggesting dependence to Nrf2. We observed no cancer promoting effect in KPC::Keap1 CKO::Nrf2+/- mice. Pancreatic cancer cell lines derived from these mice showed increased expression of Nrf2 target genes as well as decreased expression of cytokeratin family genes, indicating possible reprogramming of cellular phenotype.
Hepatic tumor and Nrf2 activation by impaired autophagy(Fostering Joint International Research)

Taguchi Keiko, Kensler Thomas W., Columbano Amedeo, Cuadrado Antonio

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Fund for the Promotion of Joint International Research (Fostering Joint International Research)

Institution: Tohoku University

2016 - 2018

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Nrf2 knockout rats were used to examine contribution of a transcription factor Nrf2 in three kinds of chemical hepatocarcinogenesis models. Partial hepatectomy and DNA extraction from tissue sections by laser capture microdissection were learned from Professor Amedeo Columbano in University of Cagliari, Italy. Keap1-independent Nrf2 activation was discussed with Professor Antonio Cuadrado in Autonomous University of Madrid in Madrid, Spain. Nrf2 activation in Aflatoxin B1-induced liver tumor models was discussed with Professor Thomas Kensler in Johns Hopkins University in Baltimore, USA.
Hepatic tumor and Nrf2 activation by impaired autophagy

Taguchi Keiko

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (C)

Institution: Tohoku University

2014/04/01 - 2017/03/31

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Autophagy is a mechanism to maintain protein quality in cells. impaired autophagy leads to Nrf2 activation through aberrant accumulation of p62 protein. Autophagy-impaired mice develop hepatic tumors. In this study, Nrf2 activation contributes to tumor formations.
肝疾患における転写因子Nrf２の機能変化

田口恵子

Offer Organization: 日本学術振興会

System: 科学研究費助成事業

Category: 新学術領域研究(研究領域提案型)

Institution: 東北大学

2013/04/01 - 2015/03/31

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Nrf2 は、生体防御反応の中核を担う転写因子である。がん細胞では、Nrf2 の恒常的な活性化が認められ、Nrf2 は、がん細胞の生存を有利にしている。しかし、Nrf2 を恒常的に活性化しただけでは、がん化しない。そこで、既存の増殖シグナルであるPI3K-Akt 経路に着目した。本経路はがん抑制遺伝子であるPten 欠失により活性化する。おおよそ半数の肝臓がんでは、Pten が欠失あるいは減少している。肝臓特異的Pten 欠失（Pten-Alb）マウスは、脂肪肝、非アルコール性脂肪肝炎を経て、肝臓がんを発症するため、脂肪肝-肝臓がんモデルマウスとして利用できる。脂肪肝は現代社会における食生活の変化などによって増加傾向にあり、脂肪肝からの肝臓がん発症のメカニズムやその病態の解明は重要な課題である。また、これまでの解析から、Nrf2 は肝臓特異的Pten 欠失マウスで起こる肝臓がんの発症・進展に重要な役割を果たすことを見出している。しかし、Pten 欠失時のNrf2 の活性化メカニズムは明らかとなっていない。そこで、Pten 欠失時におこるPI3K-Akt 経路に着目し、Nrf2 のリン酸化が関与しているのではないかと疑った。そこで、これまで明らかとなったNrf2 活性化の分子メカニズムを基に、肝臓における病態との関連を含めて解析した。PtenとNrf2の二重欠失（Pten-Alb:Nrf2）マウスはPten-Albマウスでみられる脂肪肝炎の発症は抑制しなかったが、肝臓がんの発症が著しく抑制された。よって、Nrf2は脂肪肝炎から肝臓がんの移行を促進していることが明らかとなった。
Role of Nrf2 in compensatory liver proliferation after portal vein branch ligation in mice

TAGUHI Keiko

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Young Scientists (B)

Institution: Tohoku University

2012/04/01 - 2014/03/31

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Hepatectomy is a standard therapy in liver cancer patients. Massive hepatectomy is possible to lead to liver failure. Portal vein embolization increases liver size and reduces complications. Therefore, portal vein embolization is accepted before hepatectomy to prevent liver failure. Molecular mechanisms in portal vein embolization remain elusive. In this study, portal vein branch ligation is performed in mice. We found that a transcription factor Nrf2 contributes to liver proliferation. Further more, a pre-treatment of an Nrf2 activator accelerates liver hypertrophy after portal vein branch ligation. An Nrf2 activator may be effective for enhancement of hypertrophy after portal vein embolization in liver cancer patients.
Ｋｅａｐ１－Ｎｒｆ２システムとＡｋｔシグナルの相互作用と肝疾患

田口恵子

Offer Organization: 日本学術振興会

System: 科学研究費助成事業

Category: 新学術領域研究(研究領域提案型)

Institution: 東北大学

2011/04/01 - 2013/03/31

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がん抑制遺伝子であるPtenを欠損した肝臓では、脂肪肝、非アルコール性脂肪肝炎 (NASH) を経て肝細胞がん (HCC) が発生し、この病態には酸化ストレスが関与することが報告されている。現代社会における食生活の変化などによって脂肪肝が増加傾向にあることから、脂肪肝を素地とするHCC発症のメカニズムやその病態の解明は重要な課題である。そこで、本研究では、Pten-PI3K-AktシグナルとKeap1-Nrf2システムの相互作用の解明を通して脂肪肝を素地とする肝がん発症の分子メカニズムを理解することを目的とした。そのため、肝臓特異的Pten欠損マウスと、Nrf2またはKeap1欠損マウスと交配して得られる複合変異マウスを解析した。肝臓特異的なPtenとKeap1の二重欠損マウスは門脈領域に異常な胆管増生をもたらした。この表現型はNrf2を欠失することにより消去されたので、この胆管増生はNrf2に依存的であることが示された。この二重欠損マウスでは、肝臓特異的Keap1欠損マウスに比べてNrf2の活性化が増強し、Nrf2の下流遺伝子群の発現も亢進していた。Nrf2はユビキチン-プロテアソーム系による分解によって、その発現が制御されている。本研究により、酸化ストレス応答の中核を担うKeap1-Nrf2システムがPten-PI3K-Aktシグナルと機能的に相互作用して、Keap1-Cullin3複合体によるユビキチン化に加えて、β-TrCP-Cullin1複合体によるユビキチン化がNrf2の活性制御に重要な役割を果たすことが示された。
Pathogenesis by disrupting the cytoprotective system

TAGUCHI Keiko

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Young Scientists (B)

Institution: Tohoku University

2010 - 2011

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Pathogenesis by disrupting the cytoprotective system Keap1-Nrf2 system regulates a battery of cytoprotective genes in response to both endogenous and exogenous stimuli. Constitutive Nrf2 activation by Keap1 deletion leads to hyperkeratosis in the upper digestive tract. In this study, we examined impaired autophagy activates Nrf2 to cause liver injury. The results indicate that Nrf2 activation needs properly regulation by Keap1.
Molecular Mechanisms of Adaptive Responses to Food and Oxygen

YAMAMOTO Masayuki, KATSUOKA Fumiki, MINEGISHI Naoko, MOTOHASHI Hozumi, KUROKAWA Hirofumi, SUZUKI Norio, MORIGUCHI Takashi, SUZUKI Takafumi, TAGUCHI Keiko

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Creative Scientific Research

Institution: Tohoku University

2007 - 2011

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Environmental stress response system allows organisms to keep cellular homeostasis. In this study, weexamined Keap1-Nrf2-mediated oxidative and xenobiotic defense system, and identified novel molecular mechanisms for stress-sensing system and their association with diseases. We alsoidentified diverse and elaborate gene regulatory mechanisms in response to hypoxic stressthrough the comprehensive analysis of erythropoietin gene regulatory regions.

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Teaching Experience 9

地球規模課題と国際社会　筑波大学大学院
農芸化学概論II　東京大学農学部
初年度ゼミナール理科　東京大学教養学部
食品化学　東京大学農学部
食品機能化学　東京大学農学生命科学研究科
Animal Biological Chemistry and Physiology　The University of Tokyo, Graduate School of Agricultural and Life Sciences
生体分子分析化学　東北大学医学部保健学科
医化学　東北大学医学部医学科
医化学実習　東北大学医学部医学科

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Other 6

肝臓において細胞の運命を撹乱するNrf2の機能解析

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肝臓における細胞分化
酸化ストレスによる肝疾患の発症メカニズムとその予防対策

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肝疾患と予防対策
Keap1-Nrf2システムとPten-PI3K-Aktシグナルのクロストークは肝臓の増殖や分化を制御する

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Keap1-Nrf2システムとPten-PI3K-Aktシグナルのクロストークは肝臓の増殖や分化を制御する
がん抑制遺伝子Pten欠損と転写因子Nrf2の活性化

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がん抑制遺伝子Pten欠損と転写因子Nrf2の活性化
ME3738のアセトアミノフェン誘発肝傷害防御機構へのNrf2/Keap1系の介在性に

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ME3738のアセトアミノフェン誘発肝傷害防御機構へのNrf2/Keap1系の介在性に
転写因子Nrf2の恒常的活性化による癌関連遺伝子群の発現解析

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転写因子Nrf2の恒常的活性化による癌関連遺伝子群の発現解析

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