Activation and regulation of the disease-related IL-6/STAT3 signaling

2010 Fiscal Year Final Research Report

• Project/Area Number: 20390017
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: Hokkaido University
• Principal Investigator: MATSUDA Tadashi Hokkaido University, 大学院・薬学研究院, 教授 (20212219)
• Co-Investigator(Kenkyū-buntansha): MUROMOTO Ryuta 北海道大学, 大学院・薬学研究院, 助教 (30455597) ; SEKINE Yuichi 北海道大学, 大学院・薬学研究院, 助教 (20396295) ; OHBAYASHI Norihiko 北海道大学, 大学院・薬学研究院, 助教 (40421979) ; NANBO Asuka 北海道大学, 大学院・薬学研究院, 講師 (60359487)
• Project Period (FY): 2008 – 2010
• Keywords: 免疫 / がん / シグナル伝達

Research Abstract

Since we cloned interleukin-6 (IL-6) as B cell stimulatory factor 2 in 1986, IL-6 has been reported to influence cell proliferation, differentiation, and survival as well as mature cell functions. Signal transducer and activator of transcription 3 (STAT3) is a key molecule to mediate IL-6-induced cellular events. Indeed, STAT3 is activated in many tumor tissues, and the dimmer of STAT3 promotes cellular transformation, indicating that STAT3 itself can act as a proto-oncogene. In addition to oncogenesis, IL-6/STAT3 axis influences host immune systems. For example, IL-6/STAT3 axis is involved in the Toll-like receptor signaling pathways, the development and maturation of dendritic cells, and the differentiation of Th17 T-cell subset. These facts are likely to suggest that manipulation of IL-6/STAT3 signals could be suitable target for a variety of disease such as cancer and autoimmune diseases. We have energetically examined regulatory mechanisms of IL-6/STAT3-mediated signal transduction for the development of novel therapeutic strategies.

Research Products

• [Journal Article] Functional involvement of Daxx in gp130-mediated cell growth and survival in BaF3 cells. (2010)
  • Author(s): Muromoto R., M. Kuroda S. Togi Y. Sekine A. Nanbo K. Shimoda K. Oritani, T. Matsuda
  • Journal Title: Eur. J. Immunol. 40 Pages: 3570-3580
  • Peer Reviewed
• [Journal Article] Interactions of STAP-2 with Brk and STAT3 participate in cell growth of human breast cancer cells. (2010)
  • Author(s): Ikeda O., Y. Sekine, A. Mizushima, M. Nakasuji, Y. Miyasaka, C. Yamamoto, R. Muromoto, A. Nanbo, K. Oritani, A. Yoshimura, T. Matsuda
  • Journal Title: J. Biol. Chem. 285 Pages: 38093-38103
  • Peer Reviewed
• [Journal Article] Epstein-Barr virus-derived EBNA2 regulates STAT3 activation (2009)
  • Author(s): Muromoto R., O. Ikeda, K. Okabe, S. Togi, S. Kamitani, M. Fujimuro, S. Harada, K. Oritani, T. Matsuda
  • Journal Title: Biochem. Biophys. Res. Commun. 378 Pages: 439-443
  • Peer Reviewed
• [Journal Article] HDAC3 influences phosphorylation of STAT3 at serine 727 by interacting with PP2A (2009)
  • Author(s): Togi S., S. Kamitani, S. Kawakami, O. Ikeda, R. Muromoto, A. Nanbo, T. Matsuda
  • Journal Title: Biochem. Biophys. Res. Commun. 379 Pages: 616-620
  • Peer Reviewed
• [Journal Article] The exon-junction complex proteins, Y14 and MAGOH regulate STAT3 activation. (2009)
  • Author(s): Muromoto R., N. Taira, O. Ikeda, K. Shiga, S. Kamitani, S. Togi, S. Kawakami, Y. Sekine, A. Nanbo, K. Oritani, T. Matsuda
  • Journal Title: Biochem. Biophys. Res. Commun. 382 Pages: 63-68
  • Peer Reviewed
• [Journal Article] Silencing Mediator of Retinoic acid and Thyroid hormone Receptor Regulates Enhanced Activation of Signal Transducer and Activator of Transcription 3 by Epstein-Barr Virus-derived Epstein-Barr Nuclear Antigen 2 (2009)
  • Author(s): Ikeda O., S. Togi, S. Kamitani, R. Muromoto, Y. Sekine, A. Nanbo, M. Fujimuro, T. Matsuda
  • Journal Title: Biol. Pharm. Bull. 32 Pages: 1283-1285
  • Peer Reviewed
• [Journal Article] STAP-2 is phosphorylated at tyrosine-250 by Brk and modulates Brk-mediated STAT3 activation (2009)
  • Author(s): Ikeda O., Y. Miyasaka, Y. Sekine, A. Mizushima, R. Muromoto, A. Nanbo, A. Yoshimura, T. Matsuda
  • Journal Title: Biochem. Biophys. Res. Commun. 384 Pages: 71-75
  • Peer Reviewed
• [Journal Article] The protein content of an adaptor protein, STAP-2 is controlled by E3 ubiquitin ligase Cb1 (2009)
  • Author(s): Sekine Y., C. Yamamoto, O. Ikeda, R. Muromoto, A. Nanbo, K. Oritani, A. Yoshimura, T. Matsuda
  • Journal Title: Biochem. Biophys. Res. Commun. 384 Pages: 187-192
  • Peer Reviewed
• [Journal Article] Signal-Transducing Adaptor Protein-2 Regulates Stromal Cell-Derived Factor-1a-Induced Chemotaxis in T Cells. (2009)
  • Author(s): Sekine Y., O. Ikeda, S. Tsuji, C. Yamamoto, R. Muromoto, A. Nanbo, K. Oritani, A.Yoshimura, T. Matsuda
  • Journal Title: J. Immunol. 183 Pages: 7966-7974
  • Peer Reviewed
• [Journal Article] A single polymorphic amino acid replacement in Toxoplasma gondii ROP16 influences its direct Stat3 activation (2009)
  • Author(s): Yamamoto M., D. M. Standley S. Takashima H. Saiga M. Okuyama H. Kayama E. Kubo, H. Ito M. Takaura T. Matsuda D. Soldati-Favre, K. Takada
  • Journal Title: J. Exp. Med. 206 Pages: 2747-2760
  • Peer Reviewed
• [Journal Article] Development of Et, primary myelofibrosis and PV in mice expressing JAK2 V617F (2008)
  • Author(s): Shide K., Shimoda K. S., Kumano T., Karube K., Kameda T., Takenaka K., Oku S., Abe H., Katayose K. S., Kubiki Y., Kusumo K., Hasuike S., Tahara Y., Nagata K., Matsuda T., Ohshima K., Harada M., Shimoda K.
  • Journal Title: Leukemia 22 Pages: 87-95
  • Peer Reviewed
• [Journal Article] BART is essential for nuclear retention of STAT3 (2008)
  • Author(s): Muromoto R., Sekine Y., Imoto S., Ikeda O., Okayama T., Sato N., T. Matsuda
  • Journal Title: Int. Immunol. 20 Pages: 395-403
  • Peer Reviewed
• [Journal Article] KAP1 regulates type I interferon/STAT1-mediated IRF-1 gene expression (2008)
  • Author(s): Kamitani S., Ohbayashi N., Ikeda O., Togi S., Muromoto R., Sekine Y., Ohta K., Ishiyama H., T. Matsuda
  • Journal Title: Biochem. Biophys. Res. Commun. 370 Pages: 366-370
  • Peer Reviewed
• [Journal Article] Physical and functional interactions between STAT3 and KAP1 (2008)
  • Author(s): Tsuruma R., Ohbayashi N., Kamitani S., Ikeda O., Sato N., Muromoto R., Sekine Y., Oritani K., T. Matsuda
  • Journal Title: Oncogene 27 Pages: 3054-3059
  • Peer Reviewed
• [Journal Article] The IL-6 family of cytokines modulates STAT3 activation by desumoylation of PML through SENP1 induction (2008)
  • Author(s): Ohbayashi N., Kawakami S., Muromoto R., Togi S., Ikeda O., Kamitani S., Sekine Y., Honjoh T., T. Matsuda
  • Journal Title: Biochem. Biophys. Res. Commun. 371 Pages: 823-828
  • Peer Reviewed
• [Journal Article] An RNA biding protein, Y14 interacts with and modulates STAT3 activation (2008)
  • Author(s): Ohbayashi N., N. Taira S. Kawakami S. Togi N. Sato O. Ikeda S. Kamitani R. Muromoto Y. Sekine, T. Matsuda
  • Journal Title: Biochem. Biophys. Res. Commun. 372 Pages: 475-479
  • Peer Reviewed
• [Journal Article] Physical and functional interactions between ZIP kinase and UbcH5 (2008)
  • Author(s): Ohbayashi N., K. Okada, S. Kawakami, S. Togi, N. Sato, O. Ikeda, S. Kamitani, R. Muromoto, Y. Sekine, T. Kawai, S. Akira, T. Matsuda
  • Journal Title: Biochem. Biophys. Res. Commun. 372 Pages: 708-712
  • Peer Reviewed
• [Journal Article] STAP-2 negatively regulates both canonical and non-canonical NF-kB activation induced by Epstein-Barr virus-derived LMP1. (2008)
  • Author(s): Ikeda O., Y. Sekine, T. Yasui, K. Oritani, K. Sugiyma, R. Muromoto, N. Ohbayashi, A. Yoshimura, T. Matsuda
  • Journal Title: Mol. Cell. Biol. 28 Pages: 5027-5042
  • Peer Reviewed
• [Journal Article] Enhanced c-Fms/M-CSF receptor signaling and wound-healing process in bone marrow-derived macrophages of STAP-2 deficient mice (2008)
  • Author(s): Ikeda O., Y. Sekine, R. Muromoto, N. Ohbayashi, A. Yoshimura, T. Matsuda
  • Journal Title: Biol. Pharm. Bull. 31 Pages: 1790-1793
  • Peer Reviewed
• [Presentation] EJC構成タンパク質Y14,MAGOHによるSTAT3活性の制御 (2010)
  • Author(s): 志賀要,室本竜太,松田正
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 岡山
  • Year and Date: 2010-03-28
• [Presentation] P. acnes誘導性肉芽腫形成におけるTyk2の役割 (2010)
  • Author(s): 黒田誠,室本竜太,松田正
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 岡山
  • Year and Date: 2010-03-28
• [Presentation] 低分子量二重特異性ホスファターゼDUSP3によるSTAT3活性制御機構の解析 (2010)
  • Author(s): 関根勇一,松田正
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 岡山
  • Year and Date: 2010-03-28
• [Presentation] TNF-alpha誘発性NF-kappaB活性化機構における核内コリプレッサーKAP1の機能解析/KAP1 negatively regulates TNF-alpha-induced NF-kappaB activation. (2009)
  • Author(s): Kamitani S, Togi S, Ikeda O, Kawakami S, Sekine Y, Muromoto R, Matsuda T
  • Organizer: 第39回日本免疫学会総会・学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2009-12-03
• [Presentation] STAP-2 modulates activation-induced cell death by influencing caspase-8 activation. (2009)
  • Author(s): Yamamoto C, Sekine Y, Ikeda O, Yoshimura A, Matsuda T
  • Organizer: 第39回日本免疫学会総会・学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2009-12-03
• [Presentation] STAP-2 regulates the Brk-mediated STAT5 activation. (2009)
  • Author(s): Mizushima A, Ikeda O, Miyasaka Y, Sekine Y, Yoshimura A, Matsuda T
  • Organizer: 第39回日本免疫学会総会・学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2009-12-03
• [Presentation] Physical and functional interactions among STAT3, STAP-2 and Brk. (2009)
  • Author(s): Miyasaka Y, Ikeda O, Sekine Y, Mizushima A, Yoshimura A, Matsuda T
  • Organizer: 第39回日本免疫学会総会・学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2009-12-03
• [Presentation] STAP-2 negatively regulates both canonical and noncanonical NF-κB actibation induced by Epstein-Barr virus-derived latent membrane protein 1. (2008)
  • Author(s): Ikeda O, Sekine Y, Kakisaka M, Yasui T, Yoshimura A, Matsuda T
  • Organizer: 第38回日本免疫学会総会・学術集会
  • Place of Presentation: 京都
  • Year and Date: 2008-12-03
• [Presentation] KAP1 regulates type I interferon/STAT1-mediated IRF-1 gene expression (2008)
  • Author(s): Kamitani S, Muromoto R, Sekine Y, Ikeda O, Togi S, Matsuda T
  • Organizer: 第38回日本免疫学会総会・学術集会
  • Place of Presentation: 京都
  • Year and Date: 2008-12-03
• [Presentation] Daxx inhibits gp130/STAT3-mediated survival of BaF3 cells by influencing Bcl-2 expression. (2008)
  • Author(s): Muromoto R, Matsuda T
  • Organizer: 第38会日本免疫学会総会・学術集会
  • Place of Presentation: 京都
  • Year and Date: 2008-12-03
• [Presentation] STAP-2 is involved in activation-induced cell death in Jurkat T cell. (2008)
  • Author(s): Kakisaka M, Sekine Y, Ikeda O, Yoshimura A, Matsuda T
  • Organizer: 第38回日本免疫学会総会・学術集会
  • Place of Presentation: 京都
  • Year and Date: 2008-12-03
• [Presentation] The IL-6 family of cytokines modulates STAT3 activation by desumolylation of PML through SENP1 induction. (2008)
  • Author(s): Kawakami S, Muromoto R, Togi S, Ikeda O, Kamitani S, Sekine Y, Matsuda T
  • Organizer: 第38回日本免疫学会総会・学術集会
  • Place of Presentation: 京都
  • Year and Date: 2008-12-03
• [Presentation] An RNA binding protein, Y14 interacts with and modulates STAT3 activation. (2008)
  • Author(s): Taira N, Kawakami S, Togi S, Ikeda O, Kamitani S, Muromoto R, Sekine Y, Matsuda T
  • Organizer: 第38回日本免疫学会総会・学術集会
  • Place of Presentation: 京都
  • Year and Date: 2008-12-03
• [Presentation] STAP-2 regulates integrin-mediated T-cell adhesion through protein degradation of FAK. (2008)
  • Author(s): Matsuda T, Ikeda O, Sekine Y
  • Organizer: Experimental Biology
  • Place of Presentation: San Diego, USA.
  • Year and Date: 2008-04-07
• [Presentation] アダプター分子STAP-2 による M-CSF レセプターシグナル伝達系の制御 (2008)
  • Author(s): 池田収,関根勇一,柿坂道範,松田正
  • Organizer: 日本薬学会第128年回
  • Place of Presentation: 横浜
  • Year and Date: 2008-03-26
• [Presentation] インターフェロンシグナル制御における核内コリプレッサーKAP1の機能解析 (2008)
  • Author(s): 上谷晋也,松田正
  • Organizer: 日本薬学会第128年会
  • Place of Presentation: 横浜
  • Year and Date: 2008-03-26
• [Remarks] ホームページ等
  • URL: http://www.pharm.hokudai.ac.jp/eisei/top.html