Regulation mechanism of Ras signal by novel RasGAP specific to blood cells

• Project/Area Number: 16K09822
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Niigata University
• Principal Investigator: Kousuke Saito 新潟大学, 医歯学系, 助教 (30460356)
• Co-Investigator(Kenkyū-buntansha): 藤井 雅寛 新潟大学, 医歯学系, 教授 (30183099)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: RASAL3 / 血液腫瘍 / B細胞 / 骨髄系細胞 / 腫瘍抑制因子 / 遺伝子プロファイル / RasGAP / 血液細胞 / 血液系腫瘍 / 新規RasGAP / 血球細胞系 / 細胞増殖抑制 / 血液腫瘍抑制因子

Outline of Final Research Achievements

Applicants pioneered RASAL3 as a new RasGAP in the world. In human B cell lines and myeloid tumor cell lines, forced expression of RASAL3 suppressed the development of F-actin, which is important for cell motility. B-cell and myeloid cells were abnormally proliferated in 7-9-month-old aged RASAL3-deficient mice compared with wild-type mice. Splenomegaly was frequently observed in mice lacking RASAL3. Pathological analysis of lymphoid tissue of RASAL3-deficient mice revealed pathological images suggesting abnormal proliferation and infiltration of myeloid tumor cells in bone marrow, spleen and liver. These results suggest that RASAL3 suppresses human hematological tumor cell proliferation and cell motility.

Academic Significance and Societal Importance of the Research Achievements

主にB細胞および骨髄系の免疫細胞においてRASAL3が血球細胞特異的な腫瘍抑制因子であることを明らかにした。この発見により、RASAL3の発現定量により将来の血液腫瘍の発症リスクを予測できるかもしれない。血液腫瘍においてRASAL3発現を回復させる薬剤が開発されれば、血液腫瘍の治療につながる可能性がある。RASAL3の機能の解明が更に進めば、B細胞および骨髄系細胞の発生、分化および増殖機構が更に明らかになる可能性がある。

Research Products

• [Journal Article] G3BP1 inhibits ubiquitinated protein aggregations induced by p62 and USP10 (2019)
  • Author(s): Anisimov S, Takahashi M, Kakihana T, Katsuragi Y, Kitaura H, Zhang L, Kakita A, Fujii M.
  • Journal Title: Sci Rep Volume: 9(1) Issue: 1 Pages: 12896-12896
  • DOI: 10.1038/s41598-019-46237-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] USP10 is a critical factor for Tau-positive stress granule formation in neuronal cells (2019)
  • Author(s): Piatnitskaia S, Takahashi M, Kitaura H, Katsuragi Y, Kakihana T, Zhang L, Kakita A, Iwakura Y, Nawa H, Miura T, Ikeuchi T, Hara T, Fujii M
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 10591-10591
  • DOI: 10.1038/s41598-019-47033-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The regulation of NDRG2 expression during ATLL development after HTLV-1 infection. (2019)
  • Author(s): Ichikawa T, Nakahata S, Fujii M, Iha H, Shimoda K, Morishita K.
  • Journal Title: Biochim Biophys Acta Mol Basis Dis Volume: 1865 Issue: 10 Pages: 2633-2646
  • DOI: 10.1016/j.bbadis.2019.07.001
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Degradation of p47 by autophagy contributes to CADM1 overexpression in ATLL cells through the activation of NF-κB. (2019)
  • Author(s): Sarkar B, Nishikata I, Nakahata S, Ichikawa T, Shiraga T, Saha HR, Fujii M, Tanaka Y, Shimoda K, Morishita K.
  • Journal Title: Sci Rep Volume: 9 Issue: 1 Pages: 3491-3491
  • DOI: 10.1038/s41598-019-39424-7
  • NAID: 120006825908
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] USP10 Is a Driver of Ubiquitinated Protein Aggregation and Aggresome Formation to Inhibit Apoptosis. (2018)
  • Author(s): Takahashi M, Kitaura H, Kakita A, Kakihana T, Katsuragi Y, Nameta M, Zhang L, Iwakura Y, Nawa H, Higuchi M, Komatsu M, Fujii M.
  • Journal Title: iScience Volume: 30 Pages: 433-450
  • DOI: 10.1016/j.isci.2018.11.006
  • Peer Reviewed / Open Access
• [Journal Article] Distinct gene expression signatures induced by viral transactivators of different HTLV-1 subgroups that confer a different risk of HAM/TSP. (2018)
  • Author(s): Naito T, Yasunaga JI, Mitobe Y, Shirai K, Sejima H, Ushirogawa H, Tanaka Y, Nakamura T, Hanada K, Fujii M, Matsuoka M, Saito M.
  • Journal Title: Retrovirology Volume: 15 Issue: 1 Pages: 72-72
  • DOI: 10.1186/s12977-018-0454-x
  • NAID: 120006847301
  • Peer Reviewed / Open Access
• [Journal Article] MAGI-1 expression is decreased in several types of human T-cell leukemia cell lines, including adult T-cell leukemia. (2018)
  • Author(s): Kozakai T, Takahashi M, Higuchi M, Hara T, Saito K, Tanaka Y, Masuko M, Takizawa J, Sone H, Fujii M
  • Journal Title: International Journal of Hematology Volume: 107(3) Issue: 3 Pages: 337-344
  • DOI: 10.1007/s12185-017-2359-1
  • Peer Reviewed / Open Access
• [Presentation] Role of ROS in pathogenesis of HTLV-1-associated diseases. (2018)
  • Author(s): 藤井雅寛
  • Organizer: Frontiers in Retrovirology Conference 2018
  • Int'l Joint Research