Regulatory mechanisms of apoptosis and inflammation by ASK family proteins in oral carcinogenesis

2012 Fiscal Year Final Research Report

• Project/Area Number: 22390347
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Functional basic dentistry
• Research Institution: Nagasaki University (2012); The University of Tokyo (2010-2011)
• Principal Investigator: TAKEDA Kohsuke 長崎大学, 大学院・医歯薬学総合研究科, 教授 (10313230)
• Project Period (FY): 2010 – 2012
• Keywords: 発癌 / アポトーシス / 炎症 / MAPキナーゼ / ストレス応答

Research Abstract

In this research project, we investigated the roles of ASK1 family proteins including the stress-activated kinases ASK1 and ASK2 in carcinogenesis. As a result, we found that ASK2 functions both as a tumor suppressor and a tumor promoter in a context-dependent manner, such as tissues and tumor-promoting stimuli, and that ASK1 is involved in the promotion of metastasis. Furthermore, we established two genetically modified mouse strains, ASK1ASKAmice and ASK1flox/floxmice, in which endogenous ASK1 activity can be specifically inhibited by an ATP analog compound, and ASK1 can be depleted in a tissue- or cell type-specific manner, respectively.

Research Products

• [Journal Article] Atypical protein phosphatases:emerging players in cellular signaling. (2013)
  • Author(s): Sadatomi, D., Tanimura, S., Ozaki, K. and Takeda, K.
  • Journal Title: Int. J. Mol. Sci Volume: 14 Pages: 4596-612
  • Peer Reviewed
• [Journal Article] Prevention of apoptosis by mitochondrial phosphatase PGAM5 in the mushroom body is crucial for heat shock resistance in Drosophila melanogaster (2012)
  • Author(s): Ishida, Y., Sekine, Y., Oguchi, H., Chihara, T., Miura, M., Ichijo, H. and Takeda, K
  • Journal Title: PLoS ONE Volume: 7 Pages: e30265
  • Peer Reviewed
• [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: 739-49
  • Peer Reviewed
• [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: 34635-45
  • Peer Reviewed
• [Journal Article] Apoptosis signal-regulating kinase -1 inhibitor as a potent therapeutic drug for the treatment of gastric cancer (2012)
  • Author(s): Hayakawa, Y., Hirata, Y., Sakitani, K., Nakagawa, H., Nakata, W., Kinoshita, H., Takahashi, R., Takeda, K., Ichijo, H., Maeda, S. and Koike, K.
  • Journal Title: Cancer Sci. Volume: 103 Pages: 2181-5
  • Peer Reviewed
• [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
  • Peer Reviewed
• [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
  • Peer Reviewed
• [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 Transduct Volume: 2012 Pages: 931215
  • Peer Reviewed
• [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: 434-53
  • Peer Reviewed
• [Journal Article] Identification of novel ASK1 inhibitors using virtual screening. (2011)
  • Author(s): Okamoto, M., Saito, N., Kojima, H., Okabe, T., Takeda, K., Ichijo, H., Furuya, T. and Nagano, T.
  • Journal Title: Bioorg. Med. Chem. Volume: 19 Pages: 486-9
  • Peer Reviewed
• [Journal Article] Apoptosis signal-regulating kinase 1 and cyclin D1 compose a positive feedback loop contributing to tumor growth in gastric cancer. (2011)
  • Author(s): Hayakawa, Y., Hirata, Y., Nakagawa, H., Sakamoto, K., Hikiba, Y., Kinoshita, H., Nakata, W., Takahashi, R., Tateishi, K., Tada, M., Akanuma, M., Yoshida, H., Takeda, K., Ichijo, H., Omata, M., Maeda, S. and Koike, K.
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: 108 Pages: 780-5
  • Peer Reviewed
• [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: 785-92
  • Peer Reviewed
• [Journal Article] Apoptosis signal-regulating kinase 1 inhibits hepatocarcinogenesis by controlling the tumor-suppressing function of stress-activated MAPK (2011)
  • Author(s): Nakagawa, H., Hirata, Y., Takeda, K., Hayakawa, Y., Sato, T., Kinoshita, H., Sakamoto, K., Nakata, W., Hikiba, Y., Omata, M., Yoshida, H., Koike, K. Ichijo, H. and Maeda, S.
  • Journal Title: Hepatology Volume: 54 Pages: 185-95
  • Peer Reviewed
• [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: 3006-16
  • Peer Reviewed
• [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: 719-61
  • Peer Reviewed
• [Journal Article] PGAM5: a novel type of protein serine/threonine phosphatase that exists in the mitochondria (2011)
  • Author(s): Takeda, K
  • Journal Title: J. Oral Biosci Volume: 53 Pages: 122-7
  • Peer Reviewed
• [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., Nomura, H., Toyoda, T., Hashikawa, K., Noguchi, T., Takeda, K., Ichijo, H., Tsunoda, M., Funatsu, T., Ikegami, D., Narita, M., Suzuki, T. and Matsuki, N
  • Journal Title: Neurosci. Res Volume: 66 Pages: 313-20
  • Peer Reviewed
• [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: 29 Pages: 2501-14
  • Peer Reviewed
• [Journal Article] The loss of PGAM5 suppresses the mitochondrial degeneration caused by inactivation of PINK1 in Drosophila. (2010)
  • Author(s): Imai, Y., Kanao, T., Sawada, T., Kobayashi, Y., Moriwaki, Y., Ishida, Y., Takeda, K., Ichijo, H., Lu, B. and Takahashi, R.
  • Journal Title: PLoS Genet Volume: 6 Pages: e1001229
  • Peer Reviewed
• [Journal Article] H. ASK1. (2010)
  • Author(s): Matsuzawa, A., Takeda, K. and Ichijo
  • Journal Title: UCSD-Nature Molecule Pages
  • DOI: doi:10.1038/mp.a002816.01
  • Peer Reviewed
• [Journal Article] Involvement of ASK1-p38 pathway in the pathogenesis of diabetes triggered by pancreatic β cell exhaustion
  • 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: (in press)
  • Peer Reviewed
• [Presentation] ミトコンドリア機能低下の感知システムとしてのプロテインホスファターゼPGAM5の膜内切断 (2013)
  • Author(s): 武田弘資
  • Organizer: 日本薬学会第133年会
  • Place of Presentation: 横浜
  • Year and Date: 2013-03-28
• [Presentation] ミトコンドリアのストレス受容・応答機構と炎症制御 (2013)
  • Author(s): 武田弘資
  • Organizer: 創薬シンポジウム:アカデミア創薬と探索医療
  • Place of Presentation: 長崎
  • Year and Date: 2013-03-19
• [Presentation] Role of mitochondrial phosphatase PGAM5 in inflammation. (2013)
  • Author(s): Takeda, K
  • Organizer: JST-CREST International Symposium, Frontiers in Immunology and Inflammation: From Molecules to Disease
  • Place of Presentation: 東京
  • Year and Date: 2013-02-12
• [Presentation] Role of mitochondrial protein phosphatase PGAM5 in inflammation. (2013)
  • Author(s): 貞富大地、武田弘資
  • Organizer: 10th International Conference on Protein Phosphatase
  • Place of Presentation: 東京
  • Year and Date: 2013-02-08
• [Presentation] Regulation of cellular stress response by mitochondrial protein phosphatase PGAM5 (2013)
  • Author(s): Takeda, K
  • Organizer: 1st International Symposium on Protein Modifications in Pathogenic Dysregulation of Signaling
  • Place of Presentation: 東京
  • Year and Date: 2013-02-01
• [Presentation] Analysis of ASK1 in contact hypersensitivity using a chemical genetic approach. (2012)
  • Author(s): Takeda , K., Mizukami, J., Tsuboi, R., Ichijo H.
  • Organizer: The 4th Global COE Retreat in Oiso
  • Place of Presentation: 大磯
  • Year and Date: 20120204-05
• [Presentation] ミトコンドリア局在プロテインホスファターゼPGAM5によるストレス応答制御 (2012)
  • Author(s): 武田弘資
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 福岡
  • Year and Date: 2012-12-07
• [Presentation] Role of mitochondrial phosphatase PGAM5 in inflammation. (2012)
  • Author(s): Takeda, K.
  • Organizer: The 12th Biennial International Endotoxicin & Innate Immunity Society Meeting (IEIIS2012)
  • Place of Presentation: 東京
  • Year and Date: 2012-10-24
• [Presentation] アティピカル・プロテインホスファターゼPGAM5によるストレス応答制御. (2011)
  • Author(s): 武田弘資
  • Organizer: 第84回日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 20110921-24
• [Presentation] Regulation of cellular stress response by mitochondrial protein phosphatase PGAM5 (2011)
  • Author(s): Takeda, K.
  • Organizer: 9th International Conference on Protein Phosphatase.
  • Place of Presentation: 東京
  • Year and Date: 20110201-03
• [Presentation] KLHDC10によるPP5の活性制御と酸化ストレス応答 (2011)
  • Author(s): 武田弘資、関根悠介、一條秀憲
  • Place of Presentation: 大阪
  • Year and Date: 20110119-20
• [Presentation] Regulation of cellular stress response by an atypical protein phosphatase PGAM5. (2011)
  • Author(s): Takeda, K.
  • Organizer: The First Japan-Taiwan Bilateral Conference on Protein Phosphatases.
  • Place of Presentation: 岡崎
  • Year and Date: 2011-12-02
• [Presentation] ミトコンドリア局在プロテインホスファターゼPGAM5 によるストレス応答制御 (2010)
  • Author(s): 武田弘資、一條秀憲
  • Organizer: BMB2010
  • Place of Presentation: 神戸
  • Year and Date: 20101207-10
• [Presentation] ASK2はマウス食道における4-NQO誘導性発がんを促進する. (2010)
  • Author(s): 武田弘資、永田剛裕、一條秀憲
  • Organizer: 第69回日本癌学会学術総会
  • Place of Presentation: 大阪
  • Year and Date: 20100922-24
• [Presentation] 細胞のストレス応答を制御するシグナル伝達機構の解明 (2010)
  • Author(s): 武田弘資
  • Organizer: 第52回歯科基礎医学会学術大会
  • Place of Presentation: 東京
  • Year and Date: 20100920-22
• [Presentation] ミトコンドリア局在プロテインホスファターゼPGAM5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
  • Place of Presentation: 札幌
  • Year and Date: 20100616-18
• [Presentation] ASKファミリー分子によるストレス応答の制御と疾患 (2010)
  • Author(s): 武田弘資
  • Organizer: 第149回日本獣医学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2010-03-26
• [Book] Roles for the stress-responsive kinases ASK1 and ASK2 in tumorigenesis (2012)
  • Author(s): Kamiyama, M., Sato, T., Takeda, K. and Ichijo, H.
  • Total Pages: 145-154
  • Publisher: Chembiomolecular Science: At the Frontier ofChemistry and Biology, eds Shibasaki, M., Iino, M. and Osada, H. (Springer Japan)
• [Book] ストレス応答シグナルと創薬. 「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--」 (2010)
  • Author(s): 武田弘資,一條秀憲
  • Total Pages: 317-330
  • Publisher: 廣川書店
• [Remarks]
  • URL: http://www.ph.nagasaki-u.ac.jp/lab/cell/index-j.html