Details of the Researcher

PHOTO

Baird Liam
Section
Advanced Research Center for Innovations in Next-Generation Medicine
Job title
Assistant Professor
e-Rad No.
90724914

Research Areas 1

  • Life sciences / Molecular biology /

Papers 30

  1. NRF2 Activation by CDDO-Im Regulates Inflammatory and Autophagy Pathways in Human Microglial Cells

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

    Free Radical Biology and Medicine　2025/11

    Publisher: Elsevier BV

    DOI： 10.1016/j.freeradbiomed.2025.11.046 　

    ISSN： 0891-5849

  2. Systemic activation of NRF2 contributes to the therapeutic efficacy of clinically-approved KRAS-G12C anti-cancer drugs. International-journal

    Liam Baird, Lin Zhang, Takanori Hidaka, Lyu Xi, Ke Wang, Keiko Tateno, Tatsuro Iso, Takafumi Suzuki, Kazuki Kumada, Fumiki Katsuoka, Kengo Kinoshita, Masayuki Yamamoto

    British journal of cancer　133　(9)　1377-1390　2025/11

    DOI： 10.1038/s41416-025-03162-7 　

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    BACKGROUND: The development and clinical success of KRASG12C inhibitors was a landmark achievement in anti-cancer drug development, as oncogenic KRAS had long been considered an intractable therapeutic target. Patients with KRAS mutant lung cancers frequently present with co-mutations in the KEAP1-NRF2 pathway, and because genetic activation of NRF2 results in resistance to all current anti-cancer therapies, we were motivated to explore how aberrant activation of NRF2 impacts the clinical response to KRASG12C inhibitors. METHODS: A broad range of techniques, including genetic knockouts, scRNA-seq and surface plasmon resonance, were used to determine the effect of KRASG12C drugs on NRF2. RESULTS: At physiologically-relevant concentrations, both of the clinically-approved KRASG12C inhibitors Sotorasib and Adagrasib also function as inducers of NRF2. Mechanistically, the same cysteine-targeting functionality which allows these electrophilic drugs to inhibit the mutant KRASG12C protein also facilitates their binding to cysteine-based sensors in KEAP1, resulting in the upregulation of the NRF2-dependent gene expression program. CONCLUSIONS: The activation of NRF2 by KRAS-G12C inhibitors represents a unique example of anti-cancer drugs which positively regulate the activity of a protein which is normally considered to be an oncogene. In both the malignant cells of the tumour and immune cells within the microenvironment, activation of NRF2 by electrophilic KRAS inhibitors positively contributes to the clinical efficacy of these drugs by promoting anti-cancer immunity. This unprecedented situation, in which the NRF2-dependent oxidative stress response is induced globally within cancer patients, has a number of important clinical implications, particularly in relation to ongoing combination chemotherapy clinical trials, as well as for selecting patient populations which may derive the most benefit from G12Ci anti-cancer drugs.

  3. The clinical-grade CBP/ p300 inhibitor CCS1477 represses the global NRF2-dependent cytoprotective transcription program and re-sensitizes cancer cells to chemotherapeutic drugs. International-journal

    Ke Wang, Liam Baird, Masayuki Yamamoto

    Free radical biology & medicine　233　102-117　2025/06

    DOI： 10.1016/j.freeradbiomed.2025.03.034 　

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    Constitutive activation of NRF2 provides a selective advantage to malignant tumour clones through the hijacking of the NRF2-dependent cytoprotective transcriptional program, which allows the cancer cells to survive and thrive in the chemically stressful tumour niche, whilst also providing resistance to anti-cancer drugs due to the upregulation of xenobiotic metabolizing enzymes and drug efflux pumps. Through a small-molecule epigenetic screen carried out in KEAP1 mutant lung cancer cells, in this study, we identified CCS1477 (Inobrodib) to be an inhibitor of the global NRF2-dependent transcription program. Mechanistically, CCS1477 is able to repress NRF2's cytoprotective response through the inhibition of its obligate transcriptional activator partner CBP/p300. Importantly, in addition to repressing NRF2-dependent anti-oxidative stress and xenobiotic metabolizing enzyme gene expression, CCS1477 treatment is also able to reverse the chemoresistance phenotype and re-sensitize NRF2-activated tumour cells to anti-cancer drugs. Furthermore, in co-culture experiments of KEAP1 mutant cancer cells with primary human T cells, CCS1477 treatment suppressed the acquisition of the T cell exhaustion transcriptional state, which should function to augment the anti-cancer immune response. Thus, CCS1477-mediated inhibition of CBP/p300 represents a novel therapeutic strategy with which to target the currently untreatable tumours with aberrant NRF2 activation.

  4. 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

    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.

  5. Sensor systems of KEAP1 uniquely detecting oxidative and electrophilic stresses separately In vivo Peer-reviewed

    Miu Sato, Nahoko Yaguchi, Takuya Iijima, Aki Muramatsu, Liam Baird, Takafumi Suzuki, Masayuki Yamamoto

    Redox Biology　2024/11

    DOI： 10.1016/j.redox.2024.103355 　

    ISSN： 2213-2317

  6. Whole blood transcriptome analysis for age- and gender-specific gene expression profiling in Japanese individuals. International-journal

    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　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.

  7. Immunoediting of KEAP1-NRF2 mutant tumours is required to circumvent NRF2-mediated immune surveillance

    Liam Baird, Masayuki Yamamoto

    Redox Biology　67　102904-102904　2023/11

    Publisher: Elsevier BV

    DOI： 10.1016/j.redox.2023.102904 　

    ISSN： 2213-2317

  8. A NRF2-induced secretory phenotype activates immune surveillance to remove irreparably damaged cells

    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

  9. Novel NRF2-activated cancer treatments utilizing synthetic lethality. International-journal

    Liam Baird, Thomas W Kensler, Masayuki Yamamoto

    IUBMB life　2022/10/05

    DOI： 10.1002/iub.2680 　

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    The KEAP1-NRF2 pathway regulates the main inducible cellular response to oxidative and electrophilic stresses. Activating mutations in the KEAP1-NRF2 pathway occur commonly in human cancer, where they contribute to the formation of aggressive tumours that are associated with a poor prognosis for patients. An important clinical feature of these tumours is their defiance to all current anti-cancer treatment regimens, highlighting the need for the development of new therapeutic strategies to target NRF2-activated cancers. In this review, we discuss the mechanisms through which acquired NRF2 hyperactivation can result in resistance of tumours to immune checkpoint inhibitor therapies in addition to classical chemotherapeutics, and propose with examples that using a synthetic lethal strategy mediated by NRF2-target gene-dependent bioactivation of prodrugs represents a promising strategy to specifically enhance toxicity to heretofore untreatable NRF2-hyperactivated human tumours.

  10. Halofuginone micelle nanoparticles eradicate Nrf2-activated lung adenocarcinoma without systemic toxicity. International-journal

    Harit Panda, Mikiko Suzuki, Mitsuru Naito, Ritsumi Saito, Huaichun Wen, Liam Baird, Akira Uruno, Kanjiro Miyata, Masayuki Yamamoto

    Free radical biology & medicine　187　92-104　2022/07

    DOI： 10.1016/j.freeradbiomed.2022.05.017 　

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    The Keap1-Nrf2 system is the master regulator of the cellular response against oxidative and xenobiotic stresses. Constitutive activation of Nrf2 is frequently observed in various types of cancers. Nrf2 hyperactivation induces metabolic reprogramming in cancer cells, which supports the increased energy demand required for rapid proliferation and confers high-level resistance against anticancer radio/chemotherapy. Hence, Nrf2 inhibition has emerged as an attractive therapeutic strategy to counter such acquired resistance in Nrf2-activated tumors. We previously identified Halofuginone (HF) as a promising Nrf2 inhibitor. In this study, we pursued preclinical characterization of HF and found that while HF markedly reduced the viability of cancer cells, it also caused severe hematopoietic and immune cell suppression in a dose-dependent manner. Hence, to overcome this toxicity, we decided to employ a nanomedicine approach to HF. We found that encapsulation of HF into a polymeric micelle (HF micelle; HFm) largely relieved the systemic toxicity exhibited by free HF while maintaining the tumor-suppressive properties of HF. LC-MS/MS analysis revealed that the reduction in the magnitude of adverse effects was the result of the ability to release HF from the HFm core in a slow and sustained manner. These results thus support the contention that HFm will potentially counteract Nrf2-activated cancers in the clinical settings.

  11. NRF2-dependent bioactivation of mitomycin C as a novel strategy to target KEAP1-NRF2 pathway activation in human cancer. International-journal

    Liam Baird, Masayuki Yamamoto

    Molecular and cellular biology　41　(2)　2020/11/02

    DOI： 10.1128/MCB.00473-20 　

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    Activating mutations in the KEAP1-NRF2 pathway are found in approximately 25% of lung tumours, where the hijacking of NRF2's cytoprotective functions results in aggressive tumour growth, chemoresistance, and a poor prognosis for patients. There are currently no approved drugs which target aberrant NRF2 activation, which means that there is an urgent clinical need to target this orphan oncogenic pathway in human tumours. In this study, we used an isogenic pair of wild-type and Keap1 knockout cells to screen a range of chemotherapeutic and pathway targeted anti-cancer drugs in order to identify compounds which display enhanced toxicity towards cells with high levels of Nrf2 activity. Through this approach, complemented by validation across a panel of eight human cancer cells lines from a range of different tissues, we identified the DNA damaging agent mitomycin C to be significantly more toxic in cells with aberrant Nrf2 activation. Mechanistically, we found that the NRF2 target genes cytochrome P450 reductase, NQO1, and enzymes in the pentose phosphate pathway, are all responsible for the NRF2-dependent enhanced bioactivation of mitomycin C. As mitomycin C is already approved for clinical use, it represents as excellent drug repositioning candidate to target the currently untreatable NRF2 activation in human tumours.

  12. Geldanamycin-Derived HSP90 Inhibitors Are Synthetic Lethal with NRF2. International-journal

    Liam Baird, Takafumi Suzuki, Yushi Takahashi, Eiji Hishinuma, Daisuke Saigusa, Masayuki Yamamoto

    Molecular and cellular biology　40　(22)　2020/10/26

    DOI： 10.1128/MCB.00377-20 　

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    Activating mutations in KEAP1-NRF2 are frequently found in tumors of the lung, esophagus, and liver, where they are associated with aggressive growth, resistance to cancer therapies, and low overall survival. Despite the fact that NRF2 is a validated driver of tumorigenesis and chemotherapeutic resistance, there are currently no approved drugs which can inhibit its activity. Therefore, there is an urgent clinical need to identify NRF2-selective cancer therapies. To this end, we developed a novel synthetic lethal assay, based on fluorescently labeled isogenic wild-type and Keap1 knockout cell lines, in order to screen for compounds which selectively kill cells in an NRF2-dependent manner. Through this approach, we identified three compounds based on the geldanamycin scaffold which display synthetic lethality with NRF2. Mechanistically, we show that products of NRF2 target genes metabolize the quinone-containing geldanamycin compounds into more potent HSP90 inhibitors, which enhances their cytotoxicity while simultaneously restricting the synthetic lethal effect to cells with aberrant NRF2 activity. As all three of the geldanamycin-derived compounds have been used in clinical trials, they represent ideal candidates for drug repositioning to target the currently untreatable NRF2 activity in cancer.

  13. The Molecular Mechanisms Regulating the KEAP1-NRF2 Pathway. International-journal

    Liam Baird, Masayuki Yamamoto

    Molecular and cellular biology　40　(13)　2020/06/15

    DOI： 10.1128/MCB.00099-20 　

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    The KEAP1-NRF2 pathway is the principal protective response to oxidative and electrophilic stresses. Under homeostatic conditions, KEAP1 forms part of an E3 ubiquitin ligase, which tightly regulates the activity of the transcription factor NRF2 by targeting it for ubiquitination and proteasome-dependent degradation. In response to stress, an intricate molecular mechanism facilitated by sensor cysteines within KEAP1 allows NRF2 to escape ubiquitination, accumulate within the cell, and translocate to the nucleus, where it can promote its antioxidant transcription program. Recent advances have revealed that KEAP1 contains multiple stress sensors and inactivation modalities, which together allow diverse cellular inputs, from oxidative stress and cellular metabolites to dysregulated autophagy, to regulate NRF2 activity. This integration of the KEAP1-NRF2 system into multiple cellular signaling and metabolic pathways places NRF2 activation as a critical regulatory node in many disease phenotypes and suggests that the pharmaceutical modulation of NRF2's cytoprotective activity will be beneficial for human health in a broad range of noncommunicable diseases.

  14. Molecular Mechanism of Cellular Oxidative Stress Sensing by Keap1. International-journal Peer-reviewed

    Takafumi Suzuki, Aki Muramatsu, Ryota Saito, Tatsuro Iso, Takahiro Shibata, Keiko Kuwata, Shin-Ichi Kawaguchi, Takao Iwawaki, Saki Adachi, Hiromi Suda, Masanobu Morita, Koji Uchida, Liam Baird, Masayuki Yamamoto

    Cell reports　28　(3)　746-758　2019/07/16

    DOI： 10.1016/j.celrep.2019.06.047 　

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    The Keap1-Nrf2 system plays a central role in the oxidative stress response; however, the identity of the reactive oxygen species sensor within Keap1 remains poorly understood. Here, we show that a Keap1 mutant lacking 11 cysteine residues retains the ability to target Nrf2 for degradation, but it is unable to respond to cysteine-reactive Nrf2 inducers. Of the 11 mutated cysteine residues, we find that 4 (Cys226/613/622/624) are important for sensing hydrogen peroxide. Our analyses of multiple mutant mice lines, complemented by MEFs expressing a series of Keap1 mutants, reveal that Keap1 uses the cysteine residues redundantly to set up an elaborate fail-safe mechanism in which specific combinations of these four cysteine residues can form a disulfide bond to sense hydrogen peroxide. This sensing mechanism is distinct from that used for electrophilic Nrf2 inducers, demonstrating that Keap1 is equipped with multiple cysteine-based sensors to detect various endogenous and exogenous stresses.

  15. The Keap1-Nrf2 pathway: From mechanism to medical applications

    Liam Baird, Masayuki Yamamoto

    Oxidative Stress: Eustress and Distress　125-147　2019/01/01

    Publisher: Elsevier

    DOI： 10.1016/B978-0-12-818606-0.00009-2 　

  16. A Homeostatic Shift Facilitates Endoplasmic Reticulum Proteostasis through Transcriptional Integration of Proteostatic Stress Response Pathways Peer-reviewed

    Liam Baird, Tadayuki Tsujita, Eri H. Kobayashi, Ryo Funayama, Takeshi Nagashima, Keiko Nakayama, Masayuki Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　37　(4)　E00651-U199　2017/02

    DOI： 10.1128/MCB.00439.16 　

    ISSN： 0270-7306

    eISSN： 1098-5549

  17. Hyperactivation of Nrf2 in early tubular development induces nephrogenic diabetes insipidus Peer-reviewed

    Takafumi Suzuki, Shiori Seki, Keiichiro Hiramoto, Eriko Naganuma, Eri H. Kobayashi, Ayaka Yamaoka, Liam Baird, Nobuyuki Takahashi, Hiroshi Sato, Masayuki Yamamoto

    NATURE COMMUNICATIONS　8　14577　2017/02

    DOI： 10.1038/ncomms14577 　

    ISSN： 2041-1723

  18. Absolute Amounts and Status of the Nrf2-Keap1-Cul3 Complex within Cells Peer-reviewed

    Tatsuro Iso, Takafumi Suzuki, Liam Baird, Masayuki Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　36　(24)　3100-3112　2016/12

    DOI： 10.1128/MCB.00389-16 　

    ISSN： 0270-7306

    eISSN： 1098-5549

  19. NRF2 Intensifies Host Defense Systems to Prevent Lung Carcinogenesis, but After Tumor Initiation Accelerates Malignant Cell Growth Peer-reviewed

    Hironori Satoh, Takashi Moriguchi, Daisuke Saigusa, Liam Baird, Lei Yu, Hirofumi Rokutan, Keiko Igarashi, Masahito Ebina, Tatsuhiro Shibata, Masayuki Yamamoto

    CANCER RESEARCH　76　(10)　3088-3096　2016/05

    DOI： 10.1158/0008-5472.CAN-15-1584 　

    ISSN： 0008-5472

    eISSN： 1538-7445

  20. Characterizations of Three Major Cysteine Sensors of Keap1 in Stress Response Peer-reviewed

    Ryota Saito, Takafumi Suzuki, Keiichiro Hiramoto, Soichiro Asami, Eriko Naganuma, Hiromi Suda, Tatsuro Iso, Hirotaka Yamamoto, Masanobu Morita, Liam Baird, Yuki Furusawa, Takaaki Negishi, Masakazu Ichinose, Masayuki Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　36　(2)　271-284　2016/01

    DOI： 10.1128/MCB.00868-15 　

    ISSN： 0270-7306

    eISSN： 1098-5549

  21. Design, Synthesis, and Evaluation of Triazole Derivatives That Induce Nrf2 Dependent Gene Products and Inhibit the Keap1-Nrf2 Protein-Protein Interaction Peer-reviewed

    Helene C. Bertrand, Marjolein Schaap, Liam Baird, Nikolaos D. Georgakopoulos, Adrian Fowkes, Clarisse Thiollier, Hiroko Kachi, Albena T. Dinkova-Kostova, Geoff Wells

    JOURNAL OF MEDICINAL CHEMISTRY　58　(18)　7186-7194　2015/09

    DOI： 10.1021/acs.jmedchem.5b00602 　

    ISSN： 0022-2623

    eISSN： 1520-4804

  22. The spatiotemporal regulation of the Keap1-Nrf2 pathway and its importance in cellular bioenergetics Peer-reviewed

    Albena T. Dinkova-Kostova, Liam Baird, Kira M. Holmstroem, Colin J. Meyer, Andrey Y. Abramov

    BIOCHEMICAL SOCIETY TRANSACTIONS　43　602-610　2015/08

    DOI： 10.1042/BST20150003 　

    ISSN： 0300-5127

    eISSN： 1470-8752

  23. Discovery of an NRF1-specific inducer from a large-scale chemical library using a direct NRF1-protein monitoring system Peer-reviewed

    Tadayuki Tsujita, Liam Baird, Yuki Furusawa, Fumiki Katsuoka, Yoshika Hou, Satomi Gotoh, Shin-ichi Kawaguchi, Masayuki Yamamoto

    GENES TO CELLS　20　(7)　563-577　2015/07

    DOI： 10.1111/gtc.12248 　

    ISSN： 1356-9597

    eISSN： 1365-2443

  24. Hypoxia-Sensitive Reporter System for High-Throughput Screening Peer-reviewed

    Tadayuki Tsujita, Shin-ichi Kawaguchi, Takashi Dan, Liam Baird, Toshio Miyata, Masayuki Yamamoto

    TOHOKU JOURNAL OF EXPERIMENTAL MEDICINE　235　(2)　151-159　2015/02

    DOI： 10.1620/tjem.235.151 　

    ISSN： 0040-8727

    eISSN： 1349-3329

  25. Monitoring Keap1-Nrf2 interactions in single live cells Peer-reviewed

    Liam Baird, Sam Swift, David Lleres, Albena T. Dinkova-Kostova

    BIOTECHNOLOGY ADVANCES　32　(6)　1133-1144　2014/11

    DOI： 10.1016/j.biotechadv.2014.03.004 　

    ISSN： 0734-9750

    eISSN： 1873-1899

  26. Transcription Factor Nrf1 Negatively Regulates the Cystine/Glutamate Transporter and Lipid-Metabolizing Enzymes Peer-reviewed

    Tadayuki Tsujita, Vivian Peirce, Liam Baird, Yuka Matsuyama, Misaki Takaku, Shawn V. Walsh, Julian L. Griffin, Akira Uruno, Masayuki Yamamoto, John D. Hayes

    MOLECULAR AND CELLULAR BIOLOGY　34　(20)　3800-3816　2014/10

    DOI： 10.1128/MCB.00110-14 　

    ISSN： 0270-7306

    eISSN： 1098-5549

  27. Regulatory flexibility in the Nrf2-mediated stress response is conferred by conformational cycling of the Keap1-Nrf2 protein complex Peer-reviewed

    Liam Baird, David Lleres, Sam Swift, Albena T. Dinkova-Kostova

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　110　(38)　15259-15264　2013/09

    DOI： 10.1073/pnas.1305687110 　

    ISSN： 0027-8424

  28. Nrf2 impacts cellular bioenergetics by controlling substrate availability for mitochondrial respiration Peer-reviewed

    Kira M. Holmstrom, Liam Baird, Ying Zhang, Iain Hargreaves, Annapurna Chalasani, John M. Land, Lee Stanyer, Masayuki Yamamoto, Albena T. Dinkova-Kostova, Andrey Y. Abramov

    BIOLOGY OPEN　2　(8)　761-770　2013/08

    DOI： 10.1242/bio.20134853 　

    ISSN： 2046-6390

  29. Diffusion dynamics of the Keap1-Cullin3 interaction in single live cells Peer-reviewed

    Baird L, Dinkova-Kostova AT

    Biochem Biophys Res Commun　433　58-65　2013/03

    DOI： 10.1016/j.bbrc.2013.02.065 　

  30. The cytoprotective role of the Keap1-Nrf2 pathway Peer-reviewed

    Liam Baird, Albena T. Dinkova-Kostova

    ARCHIVES OF TOXICOLOGY　85　(4)　241-272　2011/04

    DOI： 10.1007/s00204-011-0674-5 　

    ISSN： 0340-5761

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Research Projects 2

  1. Stress Sensor Mechanism by the Keap1-Nrf2 System

    Suzuki Takafumi, YAMAMOTO Masayuki, ISO Tatsuro, MURAMATSU Aki, SAITO Ryota, BAIRD Liam, SUDA Hiromi, MORITA Masanobu

    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

    2017/04/01 - 2019/03/31

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    The Keap1-Nrf2 system plays a central role in the oxidative stress response, however the identity of the reactive oxygen species sensor within Keap1 remains poorly understood. Here, we show that a Keap1 mutant lacking eleven cysteine residues retains the ability to target Nrf2 for degradation, but is unable to respond to cysteine-reactive Nrf2 inducers. Of the eleven mutated cysteine residues, we found that four are important for sensing hydrogen peroxide. Our analyses revealed that Keap1 utilizes the cysteine residues redundantly to set up an elaborate fail-safe mechanism in which specific combinations of these four cysteine residues can form a disulfide bond to sense hydrogen peroxide. Importantly, this sensing mechanism is distinct from that used for electrophilic Nrf2 inducers, demonstrating that Keap1 is equipped with multiple cysteine-based sensors to detect various endogenous and exogenous stresses.

  2. An investigation into the mechanism regulating the oxidative stress-dependent activation of the Keap1-Nrf2 pathway

    Baird Liam, Yamamoto Masayuki, Suzuki Takafumi

    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

    2016/04/01 - 2019/03/31

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    The Keap1-Nrf2 pathway is the body’s principle inducible defense against electrophilic and oxidative stress, and as such plays an important role in cellular homeostasis and human health. In order to study the molecular mechanism of Keap1-dependent Nrf2 regulation, I used a new mouse model of Nrf2 activation, in which the weak binding DLG motif has been mutated into an additional ETGE motif, which binds tightly to Keap1. Analysis of this mouse revealed no change in the oxidative stress response, suggesting that the release of the DLG motif is not required for Nrf2 activation in response to electrophilic inducers. This approach was complemented by in vitro studies of the Keap1-Cul3 complex, which revealed that the majority of Nrf2 inducers do not impact the composition of the Keap1-Cul3 complex.