RNAiスクリーニングによる浸透圧応答性キナーゼの活性制御因子群の探索

• Project/Area Number: 20657036
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Cell biology
• Research Institution: The University of Tokyo
• Principal Investigator: 一條 秀憲 The University of Tokyo, 大学院・薬学系研究科, 教授 (00242206)
• Project Period (FY): 2008 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥3,300,000 (Direct Cost: ¥3,300,000); Fiscal Year 2009: ¥1,600,000 (Direct Cost: ¥1,600,000); Fiscal Year 2008: ¥1,700,000 (Direct Cost: ¥1,700,000)
• Keywords: ストレス応答 / 浸透圧 / ASK

Research Abstract

近年、SPAK/OSR1を制御する分子の変異により遺伝性の高血圧を発症することが明らかになった。これは、細胞の浸透圧応答とイオンバランスの制御がヒトの病態と深く関わることを示す一例である。本研究の結果得られた分子群により説明される浸透圧応答メカニズムはこのような病態の理解と治療に新たな道を拓くものになると期待できる。本年度は、ショウジョウバエのRNAiスクリーニング系の立ち上げ、脱リン酸化酵素など特殊な注目分子に限定したスモールスケールのスクリーニング、そして全ゲノムの網羅的なスクリーニングへと段階的に進めて、細胞レベルの浸透圧ストレス応答の受容、情報伝達、応答に関わる分子群を遺伝学的に同定した。特にS2細胞のRNAiスクリーニングでは、ASK3やSPAK/OSR1の活性制御に関与する分子が明らかになった。また、ターゲットを絞り込んだスモールスケールのスクリーニングを行い、全遺伝子スケールにおけるスクリーニングのために、ハイスループット化が可能な方法の開発を着実に進めることができた。

Research Products

• [Journal Article] Hyperactivity in novel environment with increased dopamine and impaired novelty preference in apoptosis signal-regulating kinase 1 (ASK1)-deficient mice (2010)
  • Author(s): Kumakura, K., et al.
  • Journal Title: Neurosci.Res. 66 Pages: 313-320
  • Peer Reviewed
• [Journal Article] Apoptosis Signal-Regulating Kinase 1 regulates colitis and colitis-associated tumorigenesis via the innate immune responses (2010)
  • Author(s): Hayakawa, Y., et al.
  • Journal Title: Gastroenterology 138 Pages: 1055-1067
  • Peer Reviewed
• [Journal Article] Reciprocal negative regulation of PDK1 and ASK1 signaling by direct interaction and phosphorylation (2010)
  • Author(s): Seong, H.A., et al.
  • Journal Title: J.Biol.Chem. 285 Pages: 2397-2414
  • Peer Reviewed
• [Journal Article] (2010)
  • Author(s): 武田弘資, 他
  • Journal Title: 創薬科学の魅力-東京大学大学院薬学系研究科からの発信-(廣川書店) Pages: 317-333
• [Journal Article] Apoptosis Signal-Regulating Kinase (ASK)-1 Mediates Apoptosis through activation of JNK1 following Engagement of Membrane Immunoglobulin (2009)
  • Author(s): Furuhata, M.
  • Journal Title: Exp.Cell.Res. 315 Pages: 3467-3476
  • Peer Reviewed
• [Journal Article] Selective activation of the p38 MAPK pathway by synthetic monophosphoryl lipid A. (2009)
  • Author(s): Cekic, C., et al.
  • Journal Title: J.Biol.Chem. 284 Pages: 31982-31991
  • Peer Reviewed
• [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, et al.
  • Journal Title: Mol.Cell 36 Pages: 805-818
  • Peer Reviewed
• [Journal Article] A TNF- and c-Cbl-dependent FLIP(S)-degradation pathway and its function in Mycobacterium tuberculosis-induced macrophage apoptosis (2009)
  • Author(s): Kundu M, et al.
  • Journal Title: Nat.Immunol. 10 Pages: 918-926
  • Peer Reviewed
• [Journal Article] Critical role of apoptosis signal-regulating kinase 1 in aldosterone/salt-induced cardiac inflammation and fibrosis (2009)
  • Author(s): Nakamura, T., et al.
  • Journal Title: Hypertension 54 Pages: 544-551
  • Peer Reviewed
• [Journal Article] Mitochondrial Phosphoglycerate mutase 5 uses alternate catalytic activity as a protein serine/threonine phosphatase to activate ASK1 (2009)
  • Author(s): Takeda, K., et al.
  • Journal Title: Proc.Natl.Acad.Sci.USA. 13 Pages: 653-664
  • Peer Reviewed
• [Journal Article] Serine 58 of 14-3-3{zeta} is a molecular switch regulating ASK1 and oxidant stress-induced cell death (2009)
  • Author(s): Zhou, J., et al.
  • Journal Title: Mol.Cell.Biol. 29 Pages: 4167-4176
  • Peer Reviewed
• [Journal Article] Targeting ASK1 in ER stress-related Neurodegenerative Diseases (2009)
  • Author(s): Homma, K., et al.
  • Journal Title: Expert Opinion on Therapeutic Targets 13 Pages: 653-664
  • Peer Reviewed
• [Journal Article] Signaling pathways in invertebrate immune and stress response (2009)
  • Author(s): Hatanaka, R., et al.
  • Journal Title: Invertebrate Survival Journal 6 Pages: 32-43
  • Peer Reviewed
• [Journal Article] The roles of ASK family proteins in stress responses and diseases (2009)
  • Author(s): Hattori, K., et al.
  • Journal Title: Cell Communication and Signaling 7 Pages: 9-9
  • Peer Reviewed
• [Journal Article] Stress-Activated MAP Kinase Cascades in Cellular Senescence (2009)
  • Author(s): Maruyama, J., et al.
  • Journal Title: Curr.Med.Chem. 16 Pages: 1229-1235
  • Peer Reviewed
• [Journal Article] Guidelines for the use and interpretation of assays for monitoring cell death in higher eukaryotes (2009)
  • Author(s): Galluzzi, L., et al.
  • Journal Title: Cell Death Differ. 16 Pages: 1093-1107
  • Peer Reviewed
• [Journal Article] Oxidizable residues mediating protein stability and cytoprotective interaction of DJ-1 with apoptosis signal-regulating kinase 1 (2009)
  • Author(s): Waak, J., et al
  • Journal Title: J.Biol.Chem. 284 Pages: 14245-14257
  • Peer Reviewed
• [Journal Article] ASK1 and ASK2 differentially regulate the counteracting roles of apoptosis and inflammation in tumorigenesis (2009)
  • Author(s): Iriyama, T., et al.
  • Journal Title: EMBO J. 28 Pages: 843-853
  • Peer Reviewed
• [Journal Article] USP 14 inhibits ER-associated degradation via interaction with IRE1 alpha (2009)
  • Author(s): Nagai, A., et al.
  • Journal Title: Biochem.Biophys.Res.Commun. 379 Pages: 995-1000
  • Peer Reviewed
• [Journal Article] (2009)
  • Author(s): Nishitoh, H., et al.
  • Journal Title: Protein Misfolding Disorders : A Trip into the ER (ed Hetz, C.)(Bentham Science Publishers) Pages: 94-102
• [Journal Article] Signaling pathways in inbertebrate immune and stress response. (2009)
  • Author(s): Hatanaka, R., et al.
  • Journal Title: Invertebrate Survival Journal 6 Pages: 32-43
  • Peer Reviewed
• [Journal Article] The roles of ASK family proteins in stress responses and diseases. (2009)
  • Author(s): Hattori, K., et al.
  • Journal Title: Cell Communication and Signaling (In press)
  • Peer Reviewed
• [Journal Article] Stress-Activated MAP Kinase Cascades in Cellular Senescence. (2009)
  • Author(s): Maruyama, J.,et al.
  • Journal Title: Curr. Med. Chem. 16 Pages: 1229-1235
  • Peer Reviewed
• [Journal Article] Guidelines for the use and interpretation of assays for monitoring cell death in higher eukaryotes. (2009)
  • Author(s): Galluzzi, L., et al.
  • Journal Title: Cell Death Differ. (In press)
  • Peer Reviewed
• [Journal Article] Oxidizable residues mediating protein stability and cytoprotective interaction of DJ-1 with apoptosis signal-regulating kinase 1. (2009)
  • Author(s): Waak, J., et al
  • Journal Title: J. Biol. Chem. (In press)
  • Peer Reviewed
• [Journal Article] ASK1 and ASK2 differentially regulate the counteracting roles of apoptosis and inflammation in tumorigenesis. (2009)
  • Author(s): Iriyama, T., et al.
  • Journal Title: EMBO J., 28 Pages: 843-853
  • Peer Reviewed
• [Journal Article] USP14 inhibits ER-associated degradation via interaction with IRE1alpha. (2009)
  • Author(s): Nagai, A., et al.
  • Journal Title: Biochem. Biophys. Res. Commun., 379 Pages: 995-1000
  • Peer Reviewed
• [Journal Article] Deletion of apoptosis signal-regulating kinase 1 attenuates acetaminophen-induced liver injury by inhibiting c-jun n-terminal kinase activation. (2008)
  • Author(s): Nakagawa, H., et al.
  • Journal Title: Gastroenterology 135 Pages: 1047-1051
  • Peer Reviewed
• [Journal Article] Olmesartan prevents cardiovascular injury and hepatic steatosis in obesity and diabetes, accompanied by Apoptosis Signal regulating Kinase-1 inhibition. (2008)
  • Author(s): Yamamoto, E., et al.
  • Journal Title: Hypertension 52 Pages: 573-580
  • Peer Reviewed
• [Journal Article] Molecular Mechanism of Reactive Oxygen Species-dependent ASK1 Activation in Innate Immunity. (2008)
  • Author(s): Yamauchi, S., et al.
  • Journal Title: Immune Network 8 Pages: 1-6
  • Peer Reviewed
• [Journal Article] ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1. (2008)
  • Author(s): Nishitoh, H., et al.
  • Journal Title: Genes Dev. 22 Pages: 1451-1464
  • Peer Reviewed
• [Journal Article] Requirement of reactive oxygen species-dependent activation of ASK1-p38 MAP kinase pathway for extracelluler ATP-induced apoptosis in macrophage. (2008)
  • Author(s): Noguchi, T., et al.
  • Journal Title: J. Biol. Chem. 283 Pages: 7657-7665
  • Peer Reviewed
• [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. et al.
  • Journal Title: Biochim. Biophys. Acta. 1780 Pages: 1325-1336
  • Peer Reviewed
• [Journal Article] Signaling pathways from membrane lipid rafts to JNK1 activation in reactive nitrogen species-induced non-apoptotic cell death. (2008)
  • Author(s): Wu, Y., et al.
  • Journal Title: Cell Death Differ. 15 Pages: 386-397
  • Peer Reviewed
• [Journal Article] Apoptosis signal-regulating kinase 1 (ASK1)/p38 signaling pathway negatively regulates physiological hypertrophy. (2008)
  • Author(s): Taniike, M., et al.
  • Journal Title: Circulation 117 Pages: 545-552
  • Peer Reviewed
• [Journal Article] Apoptosis Signal-regulating Kinase 1 (ASK1) in stress and immune response. (2008)
  • Author(s): Takeda, K., et al.
  • Journal Title: Annu. Rev. Pharmacol. Toxicol. 48 Pages: 199-225
  • Peer Reviewed
• [Presentation] ASK family signaling in stress and disease (2010)
  • Author(s): 一條秀憲
  • Organizer: University of Lausanne Seminar
  • Place of Presentation: Zurich, Switzerland
  • Year and Date: 2010-03-31
• [Presentation] ASK family signaling in stress and disease (2010)
  • Author(s): 一條秀憲
  • Organizer: Emory University Seminar
  • Place of Presentation: Atlanta, USA
  • Year and Date: 2010-03-15
• [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] 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
• [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] ASK-dependent stress signaling in cell death inflammation, and disease (2009)
  • Author(s): 一條秀憲
  • Organizer: pfizer Seminar
  • Place of Presentation: USA
  • Year and Date: 2009-03-23
• [Presentation] Stress Signaling in Cell Death, Inflammation and Disease (2009)
  • Author(s): 一條秀憲
  • Organizer: 日米シンポジウム
  • Place of Presentation: 新潟
• [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: 2008-05-27
• [Presentation] ストレスシグナルと発がん(モーニングレクチャー) (2008)
  • Author(s): 一條秀憲
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
• [Presentation] 筋委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
  • Place of Presentation: 神戸