Molecular Mechanisms of Tumorigenesis, Invasion, and Metastasis by the Small GTPase Ral

• Project/Area Number: 16K08574
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Tohoku University
• Principal Investigator: Ryutaro Shirakawa 東北大学, 加齢医学研究所, 助教 (50581039)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: Ral / RalGAP / Ras / 口腔扁平上皮がん / 膵臓がん / 低分子量GTP結合タンパク質 / 低分子量GTP結合蛋白質 / 癌

Outline of Final Research Achievements

In this study, we analyzed the molecular mechanisms of oncogenesis by activation of the small GTPase Ral. Constitutive activation of Ral by the reduction of RalGAP expression is involved in promoting the migration and invasion of oral squamous cell carcinoma cells and pancreatic cancer cells. In addition, expression of RalGAPα2 is reduced in oral cancer tissue, possibly due to DNA and histone modifications in the promoter region of RalGAPα2 gene.

Academic Significance and Societal Importance of the Research Achievements

Rasファミリーの低分子量Gタンパク質Ralは、多くのがんで活性化されており、その阻害剤が開発される（Yan et al. Nature, 2014）など非常に注目されている。本研究ではRalの抑制性調節因子であるRalGAPの発現が、がんにおいて転写レベルで低下しており、それがRalの高度な活性化につながることを示した。Ralの機能制御機構の理解は新しいタイプの抗がん薬の開発につながる可能性がある。

Research Products

• [Journal Article] C2 Domains of Munc13-4 Are Crucial for Ca2+-Dependent Degranulation and Cytotoxicity in NK Cells. (2018)
  • Author(s): Na-Ryum Bin, Ke Ma, Chi-Wei Tien, Siyan Wang, Dan Zhu, Seungmee Park, Ekaterina Turlova, Kyoko Sugita, Ryutaro Shirakawa, Peter van der Sluijs, Hisanori Horiuchi, Hong-Shuo Sun, Philippe P. Monnier, Herbert Y. Gaisano and Shuzo Sugita
  • Journal Title: J Immunol. Volume: 20 Issue: 2 Pages: 700-713
  • DOI: 10.4049/jimmunol.1800426
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Human CTL-based functional analysis shows the reliability of a munc13-4 protein expression assay for FHL3 diagnosis (2018)
  • Author(s): Shibata Hirofumi、Yasumi Takahiro、Shimodera Saeko、Hiejima Eitaro、Izawa Kazushi、Kawai Tomoki、Shirakawa Ryutaro、Wada Taizo、Nishikomori Ryuta、Horiuchi Hisanori、Ohara Osamu、Ishii Eiichi、Heike Toshio
  • Journal Title: Blood Volume: 131 Issue: 18 Pages: 2016-2025
  • DOI: 10.1182/blood-2017-10-812503
  • Peer Reviewed
• [Journal Article] Human CTL-based functional analysis shows the reliability of a munc13-4 protein expression assay for FHL3 diagnosis (2018)
  • Author(s): Shibata H, Yasumi T, Shimodera S, Hiejima E, Izawa K, Kawai T, Shirakawa R, Wada T, Nishikomori R, Horiuchi H, Ohara O, Ishii E, Heike T
  • Journal Title: Blood Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Metformin directly binds the alarmin HMGB1 and inhibits its proinflammatory activity (2017)
  • Author(s): Horiuchi T, Sakata N, Narumi Y, Kimura T, Hayashi T, Nagano K, Liu K, Nishibori M, Tsukita S, Yamada T, Katagiri H, Shirakawa R, Horiuchi H
  • Journal Title: J Biol Chem Volume: 292 Pages: 8436-8446
  • Peer Reviewed
• [Journal Article] A CD57+ CTL degranulation assay effectively identifies familial hemophagocytic lymphohistiocytosis type 3 patients (2017)
  • Author(s): Masayuki Hori, Takahiro Yasumi, Saeko Shimodera, Hirofumi Shibata, Eitaro Hiejima, Hirotsugu Oda, Kazushi Izawa, Tomoki Kawai, Masataka Ishimura, Naoko Nakano, Ryutaro Shirakawa, Ryuta Nishikomori, Hidetoshi Takada, Satoshi Morita, Hisanori Horiuchi, Osamu Ohara, Eiichi Ishii, and Toshio Heike
  • Journal Title: Journal of Clinical Immunology Volume: 37 Issue: 1 Pages: 92-99
  • DOI: 10.1007/s10875-016-0357-3
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 蛍光蛋白質融合Golginを用いたゴルジ内膜輸送機構の解析 (2018)
  • Author(s): 後藤孝太 白川龍太郎 堀内久徳
  • Organizer: 第91回日本生化学会大会
• [Presentation] Metformin directly binds the alarmin HMGB1 and inhibits its proinflammatory activity (2017)
  • Author(s): Natsumi Sakata, Takahiro Horiuchi, Yoshihiro Narumi, Tomohiro Kimura, Ryutaro Shirakawa, and Hisanori Horiuchi
  • Organizer: 東北大学 知のフォーラム
  • Int'l Joint Research
• [Presentation] Metformin directly binds the alarmin HMGB1 and inhibits its proinflammatory activity (2017)
  • Author(s): Natsumi Sakata, Takahiro Horiuchi, Yoshihiro Narumi, Tomohiro Kimura, Takashi Hayashi, Keisuke Nagano, Keyue Liu, Masahiro Nishibori, Sohei Tsukita, Tetsuya Yamada, Hideki Katagiri, Ryutaro Shirakawa, and Hisanori Horiuchi
  • Organizer: 日本生化学会東北支部 第83回 例会・シンポジウム
• [Presentation] Metformin directly binds the alarmin HMGB1 and inhibits its proinflammatory activity (2017)
  • Author(s): Natsumi Sakata, Takahiro Horiuchi, Yoshihiro Narumi, Tomohiro Kimura, Takashi Hayashi, Keisuke Nagano, Keyue Liu, Masahiro Nishibori, Sohei Tsukita, Tetsuya Yamada, Hideki Katagiri, Ryutaro Shirakawa, and Hisanori Horiuchi
  • Organizer: 12th International Symposium of the Institute Network
  • Int'l Joint Research
• [Presentation] Metformin directly binds the alarmin HMGB1 and inhibits its proinflammatory activity (2017)
  • Author(s): Natsumi Sakata, Takahiro Horiuchi, Yoshihiro Narumi, Tomohiro Kimura, Takashi Hayashi, Keisuke Nagano, Keyue Liu, Masahiro Nishibori, Sohei Tsukita, Tetsuya Yamada, Hideki Katagiri, Ryutaro Shirakawa, and Hisanori Horiuchi
  • Organizer: 2017年度生命科学系学会合同大会(第90回日本生化学会大会)
• [Remarks] 東北大学 加齢医学研究所 加齢制御研究部門 基礎加齢研究分野
  • URL: http://www2.idac.tohoku.ac.jp/dep/mcb/index.html
• [Remarks] 東北大学加齢医学研究所 基礎加齢研究分野
  • URL: http://www2.idac.tohoku.ac.jp/dep/mcb/index.html