Drug development by the molecular mechanism-based analysis of stress signaling

2013 Fiscal Year Final Research Report

• Project/Area Number: 20229004
• Research Category: Grant-in-Aid for Scientific Research (S)
• Allocation Type: Single-year Grants
• Research Field: Biological pharmacy
• Research Institution: The University of Tokyo
• Principal Investigator: ICHIJO Hidenori 東京大学, 薬学研究科(研究院), 教授 (00242206)
• Co-Investigator(Kenkyū-buntansha): NAGURO Isao 東京大学, 大学院薬学系研究科, 講師 (80401222) ; NISHITOH Hideki 宮崎大学, 医学部, 教授 (00332627)
• Project Period (FY): 2008-05-12 – 2013-03-31
• Keywords: ストレス / ASKファミリー / MAPキナーゼ / アポトーシス / 浸透圧

Research Abstract

The stress response is one of the most fundamental biological processes, and its disruption results in a wide variety of diseases. We demonstrated that ASK family kinases, including ASK1, ASK2 and ASK3, play pivotal roles in the recognition of physico-chemical stresses and induction of cellular stress responses. Here, we found through the analysis of ASK1 signalosome components that ASK1 activity is tightly regulated by ubiquitination by Roquin-2 E3 ligase and USP9X deubiquitinating enzyme. ASK3, a recently identified ASK family member, was found to exhibit a bidirectional change in its activity in response to osmotic stress. Furthermore, we have found the SOD1-Derlin-1 interaction functions as an intracellular zinc concentration sensor that converts zinc deficiency into mild ER stress and induces a physiological ER stress response to maintain zinc homeostasis. These findings will shed light on the development of diagnosis, prevention and treatment of various stress-related diseases.

Research Products

• [Journal Article] The DEAH-Box RNA Helicase DHX15 activates NF-κB and MAPK signaling downstream of MAVS during antiviral responses (2014)
  • Author(s): Mosallanejad, K., Sekine, Y., Ishikura-Kinoshita, S., Kumagai, K., Nagano, T., Matsuzawa, A., Takeda, K., Naguro, I. and Ichijo, H.
  • Journal Title: Sci. Signal. Volume: 7 Pages: ra40
  • DOI: 10.1126/scisignal.2004841
• [Journal Article] ASK1 promotes the contact hypersensitivity response through IL-17 production (2014)
  • Author(s): Mizukami, J. Sato, T., Camps, M., Ji, H., Rueckle, T., Swinnen, D., Tsuboi, R., Takeda, K. and Ichijo, H
  • Journal Title: Sci. Rep. Volume: 4 Pages: 4714
  • DOI: 10.1038/srep04714
• [Journal Article] Roquin-2 promotes ubiquitin-mediated degradation of ASK1 to regulate stress responses (2014)
  • Author(s): Maruyama, T., Araki, T., Kawarazaki, Y., Naguro, I., Heynen, S., Aza-Blanc, P., Ronai, Z., Matsuzawa, A. and Ichijo, H.
  • Journal Title: Sci. Signal. Volume: 7 Pages: ra8
  • DOI: 10.1126/scisignal.2004822
• [Journal Article] Apoptosis Signal-Regulating Kinase 1 (ASK1) as a therapeutic target (2014)
  • Author(s): Kawarazaki, Y., Ichijo, H. and Naguro, I.
  • Journal Title: Expert Opinion on Therapeutic Targets Volume: 18 Pages: 651-664
  • DOI: 10.1517/14728222.2014.896903
• [Journal Article] SOD1 as a molecular switch for initiating the homeostatic ER stress response under zinc deficiency (2013)
  • Author(s): Homma, K., Fujisawa, T., Tsuburaya, N., Yamaguchi, N., Kadowaki, H., Takeda, K., Nishitoh, H., Matsuzawa, A., Naguro, I., and Ichijo, H.
  • Journal Title: Mol. Cell Volume: 52 Pages: 75-86
  • DOI: 10.1016/j.molcel.2013.08.038
• [Journal Article] Involvement of ASK1-p38 pathway in the pathogenesis of diabetes triggered by pancreatic s cell exhaustion (2013)
  • Author(s): Yamaguchi, K., Takeda, K., Kadowaki, H., Ueda, I., Namba, Y., Ouchi, Y. Nishitoh, H. and Ichijo, H.
  • Journal Title: Biochim. Biophys. Acta. Volume: 1830 Pages: 3656-3663
  • DOI: 10.1016/j.bbagen.2013.01.029
• [Journal Article] Activation mechanisms of ASK1 in response to various stresses and its significance in intracellular signaling (2013)
  • Author(s): Shiizaki, S., Naguro, I. and Ichijo, H.
  • Journal Title: Adv. Biol. Regul. Volume: 53 Pages: 135-144
  • DOI: 10.1016/j.jbior.2012.09.006
• [Journal Article] ASK3 responds to osmotic stress and regulates blood pressure by suppressing WNK1-SPAK/OSR1 signaling in the kidney (2012)
  • Author(s): Naguro, I., Umeda, T., Kobayashi, Y., Maruyama, J., Hattori, K., Shimizu, Y., Kataoka, K., Kim-Mitsuyama, S., Uchida, S., Vandewalle, A., Noguchi, T., Nishitoh, H., Matsuzawa, A., Takeda, K. and Ichijo, H.
  • Journal Title: Nat. Commun. Volume: 3 Pages: 1285
  • DOI: 10.1038/ncomms2283
• [Journal Article] The kelch repeat protein KLHDC10 regulates oxidative stress-induced ASK1 activation by suppressing PP5 (2012)
  • Author(s): Sekine, Y., Hatanaka, R., Watanabe, T., Sono, N., Iemura, S., Natsume, T., Kuranaga, E., Miura, M., Takeda, K. and Ichijo, H.
  • Journal Title: Mol. Cell Volume: 48 Pages: 692-704
  • DOI: 10.1016/j.molcel.2012.09.018
• [Journal Article] Rhomboid protease PARL mediates the mitochondrial membrane potential loss-induced cleavage of PGAM5 (2012)
  • Author(s): Sekine, S., Kanamaru, Y., Koike, M., Nishihara, A., Okada, M., Kinoshita, H., Kamiyama, M., Maruyama, J., Uchiyama, Y., Ishihara, N., Takeda, K. and Ichijo, H.
  • Journal Title: J. Biol. Chem. Volume: 287 Pages: 34635-34645
  • DOI: 10.1074/jbc.M112.357509
• [Journal Article] A novel monoclonal antibody reveals a conformational alteration shared by amyotrophic lateral sclerosis-linked SOD1 mutants (2012)
  • Author(s): Fujisawa, T., Homma, K., Yamaguchi, N., Kadowaki, H., Tsuburaya, N., Naguro, I., Matsuzawa, A., Takeda, K., Takahashi, Y., Goto, J., Tsuji, S., Nishitoh, H. and Ichijo, H.
  • Journal Title: Ann. Neurol. Volume: 72 Pages: 739-749
  • DOI: 10.1002/ana.23668
• [Journal Article] Oxidative Stress-Induced Diseases via the ASK1 Signaling Pathway (2012)
  • Author(s): Soga, M., Matsuzawa, A., Ichijo, H.
  • Journal Title: Int. J. Cell Biol. Volume: 2012 Pages: 439587
  • DOI: 10.1155/2012/439587
• [Journal Article] Roles for the stress-responsive kinase ASK1 and ASK2 in tumorigenesis (2012)
  • Author(s): Kamiyama, M., Sato, T., Takeda, K. and Ichijo, H.
  • Journal Title: Chemibiomolecular Science: At the Frontier of Chemistry and Biology, Shibasaki, M., Iino, M. Osada, H.(Eds)(Springer Japan KK) Pages: 145-153
• [Journal Article] Therapeutic targets in the ASK1-dependent stress signalling pathways (2012)
  • Author(s): Hayakawa, R., Hayakawa, T., Takeda, K. and Ichijo, H.
  • Journal Title: Proc. Jpn. Acad. Ser. B: Phys. Biol. Sci. Volume: 88 Pages: 434-453
  • DOI: 10.2183/pjab.88.434
• [Journal Article] The Phosphorylation-Dependent Regulation of Mitochondrial Proteins in Stress Responses (2012)
  • Author(s): Kanamaru, Y., Sekine S., Ichijo, H. and Takeda, K.
  • Journal Title: J. Signal Transduc. Volume: 2012 Pages: 12
  • DOI: 10.1155/2012/931215
• [Journal Article] p38 MAP kinase regulates the expression of genes in the dopamine synthesis pathway through phosphorylation of NR4A nuclear receptors (2011)
  • Author(s): Sekine,Y., Takagahara,S., Hatanaka, R., Watanabe, T., Oguchi, H., Noguchi, T., Naguro, I., Kobayashi, K., Tsunoda, M., Funatsu, T., Nomura, H., Toyoda, T., Matsuki, N., Kuranaga, E., Miura, M., Takeda, K., and Ichijo, H.
  • Journal Title: J. Cell Sci. Volume: 124 Pages: 3006-3016
  • DOI: 10.1242/jcs.085902
• [Journal Article] Regulation of anoxic death in Caenorhabditis elegans by mammalian apoptosis signal-regulating kinase (ASK) family proteins (2011)
  • Author(s): Hayakawa, T., Kato, K., Hayakawa, R., Hisamoto, N., Matsumoto, K., Takeda, K. and Ichijo, H.
  • Journal Title: Genetics Volume: 187 Pages: 785-792
  • DOI: 10.1534/genetics.110.124883
• [Journal Article] MAPKs in mammalian oxidative stress responses (2011)
  • Author(s): Runchel, C., Matsuzawa, A., and Ichijo, H.
  • Journal Title: Antioxid. Redox Signal. Volume: 15 Pages: 205-218
  • DOI: 10.1089/ars.2010.3733
• [Journal Article] Apoptosis signaling kinases: from stress response to health outcomes (2011)
  • Author(s): Takeda, K., Naguro, I., Nishitoh, H., Matsuzawa, A. and Ichijo, H.
  • Journal Title: Antioxid. Redox Signal. Volume: 15 Pages: 719-761
  • DOI: 10.1089/ars.2010.3392
• [Journal Article] CHIP-dependent termination of MEKK2 regulates temporal ERK activation required for proper hyperosmotic response (2010)
  • Author(s): Maruyama, T., Kadowaki, H., Okamoto, N., Nagai, A., Naguro, I., Matsuzawa, A., Shibuya, H., Tanaka, K., Murata, S., Takeda, K., Nishitoh, H. and Ichijo H.
  • Journal Title: EMBO J. Volume: 4 Pages: 2501-2514
  • DOI: 10.1038/emboj.2010.141
• [Journal Article] ASK1: Molecule Pages (2010)
  • Author(s): Matsuzawa, A., Takeda, K. and Ichijo, H.
  • Journal Title: UCSD-Nature Signaling Gateway
  • DOI: 10.1038/mp.a002816.01
• [Journal Article] Regulation of Apoptosis Signal-regulating Kinase 1 in redox signaling (2010)
  • Author(s): Katagiri, K., Matsuzawa, A. and Ichijo H.
  • Journal Title: Methods in Enzymology Volume: 474 Pages: 277-288
  • DOI: 10.1016/S0076-6879(10)74016-7
• [Journal Article] Ubiquitin-like sequence in ASK1 plays critical roles in the recognition and stabilization by USP9X and oxidative stress-induced cell death (2009)
  • Author(s): Nagai, H,, Noguchi, T., Homma, K., Katagiri, K., Takeda, K., Matsuzawa, A. and Ichijo H.
  • Journal Title: Mol. Cell Volume: 36 Pages: 805-818
  • DOI: 10.1016/j.molcel.2009.10.016
• [Journal Article] Mitochondrial phosphoglycerate mutase 5 uses alternate catalytic activity as a protein serine/ threonine phosphatase to activate ASK1 (2009)
  • Author(s): Takeda, K., Komuro, Y., Hayakawa, T., Oguchi, H., Ishida, Y., Murakami, S., Noguchi, T., Kinoshita, H., Sekine, Y., Iemura, S., Natsume, T., and Ichijo H.
  • Journal Title: Proc. Natl. Acad. Sci. USA. Volume: 106 Pages: 12301-12305
  • DOI: 10.1073/pnas.0901823106
• [Journal Article] ASK1 and ASK2 differentially regulate the counteracting roles of apoptosis and inflammation in tumorigenesis (2009)
  • Author(s): Iriyama, T., Takeda, K., Nakamura, H., Morimoto, Y., Kuroiwa, T., Mizukami, J., Umeda, T., Noguchi, T., Naguro, I., Nishitoh, H., Saegusa, K., Tobiume, K., Homma, T., Shimada, Y., Tsuda, H., Aiko, S., Imoto, I., Inazawa, J., Chida, K., Kamei, Y., Kozuma, S., Taketani, Y., Matsuzawa, A. and Ichijo H.
  • Journal Title: EMBO J. Volume: 28 Pages: 843-853
  • DOI: 10.1038/emboj.2009.32
• [Journal Article] USP14 inhibits ER-associated degradation via interaction with IRE1alpha (2009)
  • Author(s): Nagai, A., Kadowaki, H., Maruyama, T., Takeda, K., Nishitoh, H. and Ichijo, H.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 379 Pages: 995-1000
  • DOI: 10.1016/j.bbrc.2008.12.182
• [Journal Article] Signaling pathways in invertebrate immune and stress response (2009)
  • Author(s): Hatanaka, R., Sekine, Y., Hayakawa, T., Takeda, K. and Ichijo H.
  • Journal Title: Invertebrate Survival Journal Volume: 6 Pages: 32-43
• [Journal Article] The roles of ASK family proteins in stress responses and diseases (2009)
  • Author(s): Hattori, K., Naguro, I., Runchel, C. and Ichijo H.
  • Journal Title: Cell Communication and Signaling Volume: 7 Pages: 9
  • DOI: 10.1186/1478-811X-7-9
• [Journal Article] Stress-Activated MAP Kinase Cascades in Cellular Senescence (2009)
  • Author(s): Maruyama, J., Naguro, I., Takeda, K. and Ichijo H.
  • Journal Title: Curr. Med. Chem. Volume: 16 Pages: 1229-1235
  • DOI: 10.2174/092986709787846613
• [Journal Article] ALS-linked mutant SOD1 induces ER stress-and ASK1-dependent motor neuron death by targeting Derlin-1 (2008)
  • Author(s): Nishitoh, H., Kadowaki, H., Nagai, A., Maruyama, T., Yokota, T., Fukutomi, H., Noguchi, T., Matsuzawa, A., Takeda, K. and Ichijo H.
  • Journal Title: Genes Dev. Volume: 22 Pages: 1451-1464
  • DOI: 10.1101/gad.1640108
• [Journal Article] Molecular Mechanism of Reactive Oxygen Species-dependent ASK1 Activation in Innate Immunity (2008)
  • Author(s): Yamauchi, S., Noguchi, T. and Ichijo H.
  • Journal Title: Immune Network Volume: 8 Pages: 1-6
• [Journal Article] Redox control of cell fate by MAP kinase: physiological roles of ASK1-MAP kinase pathway in stress signaling (2008)
  • Author(s): Matsuzawa, A. and Ichijo H.
  • Journal Title: Biochim. Biophys. Acta. Volume: 1780 Pages: 1325-1336
  • DOI: 10.1016/j.bbagen.2007.12.011
• [Journal Article] Apoptosis Signal-regulating Kinase 1 (ASK1) in stress and immune response (2008)
  • Author(s): Takeda, K., Noguchi, T., Naguro, I. and Ichijo H.
  • Journal Title: Annu.Rev. Pharmacol.Toxicol. Volume: 48 Pages: 199-225
  • DOI: 10.1146/annurev.pharmtox.48.113006.094606
• [Presentation] Regulation of cell death signals by ubiquitination and deubiquitination (2013)
  • Author(s): Ichijo, H.
  • Organizer: The 35th Naito Conference The Ubiquitin-proteasome system-
  • Place of Presentation: Sapporo
  • Year and Date: 20130709-12
• [Presentation] 細胞がストレスを感じる仕組みと疾患 (2013)
  • Author(s): 一條秀憲
  • Organizer: 第37回皮膚科免疫セミナー
  • Place of Presentation: 東京
  • Year and Date: 2013-03-02
• [Presentation] ASK Family Kinases in Stress Response and Disease (2012)
  • Author(s): Hidenori Ichijo
  • Organizer: The 4th Takeda Science Foundation Symposium on Pharma Sciences "On the Frontiers of Chemical Biology"
  • Place of Presentation: Tokyo
  • Year and Date: 20121203-04
• [Presentation] ストレス応答の破綻と神経変性疾患 (2012)
  • Author(s): 一條秀憲
  • Organizer: 第39回日本脳科学会
  • Place of Presentation: 小倉
  • Year and Date: 20121006-07
• [Presentation] SOD1 as a molecular switch to initiate homeostatic ER stress response under conditions of zinc deficiency (2012)
  • Author(s): Hidenori Ichijo
  • Organizer: The 33rd Naito Conference: Oxygen Biology: Hypoxia, Oxidative Stress and Diseases
  • Place of Presentation: Sapporo
  • Year and Date: 20120626-29
• [Presentation] ALS発症のメカニズム (2012)
  • Author(s): 一條秀憲
  • Organizer: 第5回東京アンチエイジングアカデミー
  • Place of Presentation: 東京
  • Year and Date: 2012-06-21
• [Presentation] Stress signaling in cell death, infiammation and disease (2011)
  • Author(s): Hidenori Ichijo
  • Organizer: The 23th Annual Meeting of the Korean Society for Molecular and Cellular Biology
  • Place of Presentation: Korea
  • Year and Date: 20111006-07
• [Presentation] ASK-Dependent Stress Signaling in Cell Death, Inflammation and Disease (2011)
  • Author(s): Hidenori Ichijo
  • Organizer: The Uehara Memorial Foundation Symposium.2011
  • Place of Presentation: Tokyo
  • Year and Date: 2011-06-08
• [Presentation] ASK family signaling in ER stress and ALS (2010)
  • Author(s): Hidenori Ichijo
  • Organizer: APRU Research symposium on the Interface between Molecular Biology and Nano-Biology
  • Place of Presentation: Kyoto
  • Year and Date: 20101124-26
• [Presentation] ASKファミリーを介したストレスシグナルによる発がん制御 (2010)
  • Author(s): 一條秀憲,武田弘資
  • Organizer: 第69回日本癌学会学術総会シンポジウム
  • Place of Presentation: 大阪
  • Year and Date: 20100922-24
• [Presentation] ASK-dependent Stress Signaling in Cell Death, Inflammation and Disease (2010)
  • Author(s): Hidenori Ichijo
  • Organizer: ISMC2010
  • Place of Presentation: ベルギー
  • Year and Date: 20100905-09
• [Presentation] 細胞がストレスを感じる仕組みと疾患 (2010)
  • Author(s): 一條秀憲
  • Organizer: 第64回日本口腔科学会学術集会シンポジウム
  • Place of Presentation: 札幌
  • Year and Date: 20100624-25
• [Presentation] ミトコンドリア局在プロテインホスファターゼ PGM5によるストレス応答制御 (2010)
  • Author(s): 武田弘資,一條秀憲
  • Organizer: 第10回日本蛋白質科学会年会ワークショップ
  • Place of Presentation: 札幌
  • Year and Date: 20100616-18
• [Presentation] ASKファミリーによるストレス応答機構と疾患 (2010)
  • Author(s): 一條秀憲
  • Organizer: 第9回細胞死研究会
  • Place of Presentation: 京都
  • Year and Date: 20100118-19
• [Presentation] ASK family signaling in Cancer and ALS (2010)
  • Author(s): Hidenori Ichijo
  • Organizer: Biomedical Research Seminar LUMC (Liden University Medical Center)
  • Place of Presentation: オランダ
  • Year and Date: 2010-09-08
• [Presentation] ASKファミリーによるストレス応答～細胞がストレスを感じる仕組みと疾患～ (2010)
  • Author(s): 一條秀憲
  • Organizer: 第29回分子病理学研究会
  • Place of Presentation: つくば
  • Year and Date: 2010-07-31
• [Presentation] ASK family signaling in stress and disease (2010)
  • Author(s): 一條秀憲
  • Organizer: 第15回愛知県がん国際シンポジウム
  • Place of Presentation: 名古屋
  • Year and Date: 2010-03-06
• [Presentation] Stress Signaling in Cell Death, Inflammation and Disease (2009)
  • Author(s): Hidenori Ichijo
  • Organizer: 日米シンポジウム
  • Place of Presentation: 新潟
  • Year and Date: 20090212-13
• [Presentation] ASKファミリーによるストレス応答機構～浸透圧ストレス応答と血圧制御～ (2009)
  • Author(s): 一條秀憲
  • Organizer: 第8回Vascular and Brain Conference
  • Place of Presentation: 大阪
  • Year and Date: 2009-10-09
• [Presentation] Signaling through ASK1-JNK / p38 pathways (2009)
  • Author(s): Hidenori Ichijo
  • Organizer: 中国 Xiamen Universityセミナー
  • Place of Presentation: 中国
  • Year and Date: 2009-01-17
• [Presentation] ASKファミリーによるストレス応答 (2009)
  • Author(s): 一條秀憲
  • Organizer: 薬理学セミナー
  • Place of Presentation: 熊本
  • Year and Date: 2009-01-06
• [Presentation] 筋萎縮性側索硬化症における小胞体ストレス (2008)
  • Author(s): 一條秀憲
  • Organizer: BMB2008
  • Place of Presentation: 神戸
  • Year and Date: 20081209-12
• [Presentation] 神経変性の治療標的としてのストレスシグナル (2008)
  • Author(s): 一條秀憲
  • Organizer: CBI学会研究講演会「神経変性疾患の標的と創薬」
  • Place of Presentation: 東京
  • Year and Date: 2008-12-16
• [Presentation] ストレスシグナルによるアポトーシスの制御機構～細胞がストレスを感じる仕組みと疾患～ (2008)
  • Author(s): 一條秀憲
  • Organizer: 第3回山陰先進医学研究会
  • Place of Presentation: 鳥取
  • Year and Date: 2008-06-12
• [Presentation] ストレス応答の制御機構～細胞がストレスを感じる仕組みと疾患～ (2008)
  • Author(s): 一條秀憲
  • Organizer: 第6回幹細胞シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2008-05-16
• [Remarks]
  • URL: http://www.f.u-tokyo.ac.jp/~toxicol/index.html
• [Patent(Industrial Property Rights)] 筋萎縮性側索硬化症.. (ALS)の診断のための抗体 (2010)
  • Inventor(s): 西頭英起、一條秀憲
  • Industrial Property Rights Holder: 東京大学
  • Industrial Property Number: 特願 2010-111375
  • Filing Date: 2010-05-13