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Extensive influence on malignancy by cancer specific mature mRNA re-splicing

Research Project

Project/Area Number 17K07182
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Tumor biology
Research InstitutionFujita Health University

Principal Investigator

Kameyama Toshiki  藤田医科大学, 医学部, 講師 (60298544)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
KeywordsmRNA再スプライシング / エクソン・ジャンクション複合体 / RBM4a / エキシトロン / がん / スプライシング異常 / がん細胞 / 成熟mRNA再スプライシング / EJC / がん抑制遺伝子 / RNA結合因子 / 制御因子 / 癌 / 異常スプライシング / mRNA品質管理機構 / 悪性化
Outline of Final Research Achievements

We have demonstrated a novel two-step splicing process in which normally spliced TSG101 mRNA is re-spliced to generate aberrant TSG101 mRNA in cancer cells .The mRNA re-splicing implies an important mechanism that prevents deleterious extra re-splicing in normal cells. The control of the re-splicing could be promoted by unknown activator upregulated and/or repressor downregulated in cancer cells. To identify repressor candidates of mRNA re-splicing, we screened siRNA library. As a result, we have identified RBM4a and EIF4A3 proteins as a mRNA re-splicing repressor. RBM4a is also known as a tumor suppressor via controlling apoptosis, proliferation and migration. On the other hand, EIF4A3 is well known as a core factor of the exon junction complex (EJC). We postulate that global prevention of aberrant mRNA re-splicing, termination of splicing precisely, is critical for the consequent tumor suppression. These factors could be key factors to prove this hypothesis.

Academic Significance and Societal Importance of the Research Achievements

これまで、スプライシング反応が完了すると、mRNA上にはまだスプライス部位が残存するにもかかわらず、直ちに核外に輸送されタンパク質に翻訳されると考えられてきた。本研究で我々の発見した結果は、正常細胞にはスプライシング反応をきちんと停止させる機構が存在する事を新たに示唆した。
そして、その機構が破綻すると、細胞のトランスクリプトームを破綻させることにつながる事も示し、その大規模な破綻が細胞がん化など重大な疾患に結びつく可能性を示唆した点が重要である。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (20 results)

All 2019 2018 2017 Other

All Int'l Joint Research (5 results) Journal Article (4 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 4 results,  Open Access: 4 results) Presentation (10 results) (of which Int'l Joint Research: 4 results,  Invited: 2 results) Remarks (1 results)

  • [Int'l Joint Research] ウィーン天然資源大学応用遺伝 学・細胞生物学科/Viennna Biocenter Core Facilities(オーストリア)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] ウィーン天然資源大学応用遺伝学・細胞生物学科/Viennna Biocenter Core Facilities(オーストリア)

    • Related Report
      2018 Research-status Report
  • [Int'l Joint Research] Centre for Genomic Regulation(スペイン)

    • Related Report
      2018 Research-status Report
  • [Int'l Joint Research] ウィーン天然資源大学応用遺伝学・細胞生物学科/Viennna Biocenter Core Facilities(オーストリア)

    • Related Report
      2017 Research-status Report
  • [Int'l Joint Research] Centre for Genomic Regulation(スペイン)

    • Related Report
      2017 Research-status Report
  • [Journal Article] Cancer-Specifically Re-Spliced TSG101 mRNA Promotes Invasion and Metastasis of Nasopharyngeal Carcinoma2019

    • Author(s)
      Chua Huey-Huey、Kameyama Toshiki、Mayeda Akila、Yeh Te-Huei
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 20 Issue: 3 Pages: 773-773

    • DOI

      10.3390/ijms20030773

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] シスプラチン抵抗性ヒト膀胱癌細胞株の樹立と網羅的遺伝子発現解析2018

    • Author(s)
      飴本 剛之介、亀山 俊樹、日下 守、前田 明、白木 良一
    • Journal Title

      藤田学園医学会誌

      Volume: 42 Pages: 37-40

    • NAID

      120006699286

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Rearrangement of VPS13B, a causative gene of Cohen syndrome, in a case of RUNX1-RUNX1T1 leukemia with t(8;12;21).2017

    • Author(s)
      Abe A, Yamamoto Y, Katsumi A, Okamoto A, Tokuda M, Inaguma Y, Yamamoto K, Yanada M, Kanie T, Tomita A, Akatsuka Y, Okamoto M, Kameyama T, Mayeda A, Emi N.
    • Journal Title

      Int J Hematol.

      Volume: - Issue: 2 Pages: 208-212

    • DOI

      10.1007/s12185-017-2387-x

    • Related Report
      2018 Research-status Report 2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] MU314, a novel selective estrogen receptor modulator (SERM), improves estrogen-dependent depressive behaviors2017

    • Author(s)
      N Izumo、Y Ishibashi、Y Ono、M Toho、A Sumino、T Kameyama、T Morikawa、Y Shiba、Y Watanabe、T Manabe
    • Journal Title

      Global Drugs and Therapeutics

      Volume: 2 Issue: 5

    • DOI

      10.15761/gdt.1000s1004

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] EJC Core Represses Cancer-specific Mature mRNA Re-splicing: EJC As a Signal to Terminate Splicing.2019

    • Author(s)
      Yuta Ohtani, Toshiki Kameyama, Peter Venhuizen, Maria Kalyna, Akila Mayeda
    • Organizer
      Cold Spring Harbor Laboratory Meeting “EUKARYOTIC mRNA PROCESSING”
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] EJCが癌特異的な成熟 mRNA再スプライシングを抑制する:mRNAの品質管理に関わる新たな EJCの役割2019

    • Author(s)
      大谷 勇太 、亀山 俊樹、Peter Venhuizen、Maria Kalyna、前田 明
    • Organizer
      【ワークショップ】真核生物におけるストレスに応答した遺伝子発現制御とその破綻に伴う老化および疾患 第42回日本分子生物学会年会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Cancer specific aberrant mRNA re-splicing and its repressors: What are the splicing termination mechanisms destroyed in cancer cells?2019

    • Author(s)
      Toshiki Kameyama
    • Organizer
      Invited Seminar at University of Natural Resources and Life Sciences, Vienna (BOKU), Department of Applied Genetics and Cell Biology (DAGZ)
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] EJCががん特異的な成熟mRNA再スプライシングを抑制する:スプライシング正常化にはたらく新たなEJCの役割2018

    • Author(s)
      大谷勇太、亀山俊樹、前田明
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Research-status Report
  • [Presentation] Identification of Tumor Suppressor RBM4a as a Repressor of Cancer-Specific Mature mRNA Re-splicing.2018

    • Author(s)
      亀山俊樹
    • Organizer
      第77回日本癌学会学術総会
    • Related Report
      2018 Research-status Report
  • [Presentation] がん抑制因子RBM4aはがん細胞特異的成熟mRNA再スプライシングを抑制する2018

    • Author(s)
      亀山俊樹、福村和宏、井上邦夫、廣瀬哲郎、前田明
    • Organizer
      第20回日本RNA学会年会
    • Related Report
      2018 Research-status Report
  • [Presentation] A Repressor Candidate of Cancer Specific mRNA Re-splicing: A Key factor for splicing fidelity or mRNA quality control?2017

    • Author(s)
      Toshiki Kameyama1, Kazuhiro Fukumura1,2, Kunio Inoue2, Tetsuro Hirose3, Akila Mayeda1
    • Organizer
      RNA2017 The 22nd Annual Meeting of the RNA Society.
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] A Repressor Candidate of Cancer Specific mRNA Re-splicing: A Key factor for splicing fidelity or mRNA quality control?2017

    • Author(s)
      Toshiki Kameyama1, Kazuhiro Fukumura1,2, Kunio Inoue2, Tetsuro Hirose3, Akila Mayeda1.
    • Organizer
      International Symposium on the Hallmarks of Cancer: Focus on RNA
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] A Repressor Candidate of Cancer Specific mRNA Re-splicing: A Key factor for splicing fidelity or mRNA quality control?がん細胞特異的mRNA再スプライシング抑制因子の探索:スプライシングの忠実度及びmRNA品質保証関連因子2017

    • Author(s)
      亀山俊樹
    • Organizer
      第76回日本癌学会学術総会
    • Related Report
      2017 Research-status Report
  • [Presentation] がん抑制因子RBM4aはがん細胞特異的成熟mRNA再スプライシングを抑制する:mRNA品質保証の鍵となる因子か?2017

    • Author(s)
      亀山俊樹1,福村和宏1,2、井上邦夫2、廣瀬哲朗3,前田明1
    • Organizer
      生命科学系学会合同年次大会ConBio2017
    • Related Report
      2017 Research-status Report
  • [Remarks] 藤田医科大学 総合医科学研究所 遺伝子発現機構学研究部門

    • URL

      http://www.fujita-hu.ac.jp/~mayeda/

    • Related Report
      2019 Annual Research Report 2018 Research-status Report

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Published: 2017-04-28   Modified: 2021-02-19  

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