Elucidation of roles of small GTPase Ral and its negative regulator RalGAP in tumorigenesis, and cancer invasion and metastasis

• Project/Area Number: 25290041
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Tohoku University
• Principal Investigator: Horiuchi Hisanori 東北大学, 加齢医学研究所, 教授 (90291426)
• Co-Investigator(Renkei-kenkyūsha): OGAWA Osamu 京都大学, 医学研究科, 教授 (90260611) ; HIROYUKI Nishiyama 筑波大学, 人間総合科学研究科(系), 教授 (20324642) ; NAKASE Hiroshi 京都大学, 医学研究科, 講師 (60362498)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2015: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2014: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2013: ¥9,100,000 (Direct Cost: ¥7,000,000、Indirect Cost: ¥2,100,000)
• Keywords: 腫瘍 / 低分子量GTP結合蛋白質 / Ral / がん抑制遺伝子 / がん / GTP結合蛋白室 / 炎症 / GTP結合蛋白質

Outline of Final Research Achievements

We have first identified negative regulators of small GTPases, Ral, that plays important roles in human tumorigenesis; RalGAP (JBC, 2009) and reported its important role in bladder cancer progression (Oncogene, 2013). We proceeded the investigation in this investigation as follows: (1) We found that Ral and RalGAP play an important role in inflammatory bowel disease and colitis-associated colon cancer formation. (2) We identified Ral-associated kinase and have been analyzing it. (3) We investigated the mechanism of reduced expression of RalGAP in bladder cancer cells and found an involvement of an epigenetic mechanism such as DNA methylation. (4) We have prepared its conditional KO mice in our laboratory. Currently, we are preparing its tissue specific KO mice. (5) We have summarized recent findings of Ral by focusing on RalGAP and published as a review article.

Research Products

• [Journal Article] Prostaglandin E2 inhibits neutrophil extracellular trap formation through production of cyclic AMP (2016)
  • Author(s): 3.K. Shishikura, T. Horiuchi, N. Sakata, D-A Trinh, R. Shirakawa, T. Kimura, Y. Asada, H. Horiuchi*
  • Journal Title: Br J Pharmacol Volume: 173 Issue: 2 Pages: 319-331
  • DOI: 10.1111/bph.13373
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Ral GTPases: crucial mediators of exocytosis and tumourigenesis. (2015)
  • Author(s): Shirakawa R, Horiuchi H.
  • Journal Title: The Journal of Biochemistry Volume: 157 Issue: 5 Pages: 285-299
  • DOI: 10.1093/jb/mvv029
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Ral GTPases: Crucial Mediators of Exocytosis and Tumorigensis. (a review) (2015)
  • Author(s): R. Shirakawa, H. Horiuchi
  • Journal Title: J Biochem (tokyo) Volume: in press
  • Acknowledgement Compliant
• [Journal Article] Platelets are highly activated in patients of chronic thromboembolic pulmonary hypertension (CTEPH). (2014)
  • Author(s): Yaoita N, Shirakawa R, Fukumoto Y, Sugimura K, Miyata S, Miura Y, Nochioka K, Miura M, Tatebe S, Aoki T, Miyamichi-Yamamoto S, Satoh K, Kimura T, Shimokawa H, Horiuchi H.
  • Journal Title: Arterioscler Thromb Vasc Biol. Volume: 34 Issue: 11 Pages: 2486-2494
  • DOI: 10.1161/atvbaha.114.304404
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The antimalarial drugs chloroquine and primaquine inhibit pyridoxal kinase, an essential enzyme for vitamin B6 production (2014)
  • Author(s): Kimura T, Shirakawa R, Yaoita N, Hayashi T, Nagano K, Horiuchi H
  • Journal Title: FEBS letters Volume: 588 Issue: 20 Pages: 3673-3676
  • DOI: 10.1016/j.febslet.2014.08.011
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] GARNL1, a major RalGAP α subunit in skeletal muscle, regulates insulin-stimulated RalA activation and GLUT4 trafficking via interaction with 14-3-3 proteins (2014)
  • Author(s): Chen Q, Quan C, Xie B, Chen L, Zhou S, Toth R, Campbell DG, Lu S, Shirakawa R, Horiuchi H, Li C, Yang Z, MacKintosh C, Wang HY, Chen S
  • Journal Title: Cellular Signalling Volume: 26 Issue: 8 Pages: 1636-1648
  • DOI: 10.1016/j.cellsig.2014.04.012
  • Peer Reviewed / Acknowledgement Compliant
• [Remarks] 東北大学加齢医学研究所基礎加齢分野ホームページ
  • URL: http://www2.idac.tohoku.ac.jp/dep/mcb/study/ralgtpase/index.html
• [Remarks] ナンバーワン・オンリーワンの研究成果オンリーワンの研究成果
  • URL: http://www.idac.tohoku.ac.jp/ja/no1_only1/pdf/06_kiso.pdf
• [Remarks] 東北大学加齢医学研究所基礎加齢分野ホームページ
  • URL: http://www2.idac.tohoku.ac.jp/dep/mcb/