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Exploring the implications of cancer-specific mRNA re-splicing events in the robustness and catastrophe of gene expression system

Research Project

Project/Area Number 16H04705
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Tumor diagnostics
Research InstitutionFujita Health University

Principal Investigator

Mayeda Akila  藤田医科大学, 総合医科学研究所, 教授 (50212204)

Co-Investigator(Kenkyū-buntansha) 藤井 多久磨  藤田医科大学, 医学部, 教授 (10218969)
白木 良一  藤田医科大学, 医学部, 教授 (70226330)
恵美 宣彦  藤田医科大学, 医学部, 教授 (30185144)
Project Period (FY) 2016-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥16,640,000 (Direct Cost: ¥12,800,000、Indirect Cost: ¥3,840,000)
Fiscal Year 2019: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2018: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2017: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2016: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Keywords遺伝子発現調節 / スプライシング / mRNA品質管理機構 / スプライシング完了機構 / TSG101 / eIF4A3 / EJC / RNPS / PSAP / 癌 / RBM4a / 遺伝子発現 / mRNA / 品質管理機構 / p53 / プロテオーム
Outline of Final Research Achievements

We previously discovered cancer-specific mRNA re-splicing that occurs on mature spliced mRNA and generates aberrant transcripts/proteins. The mRNA re-splicing in various cancer cells implies an important mechanism that prevents deleterious extra re-splicing in normal cells. We postulated that the control of the mRNA re-splicing is promoted by a specific repressor downregulated in cancer cells. To test this hypothesis, we performed siRNA screening of repressor candidates based on mRNA re-splicing activity. We found that knockdown of eIF4A3 markedly induced mRNA re-splicing. eIF4A3 is a core component of the exon junction complex (EJC). Remarkably, we could recapitulate cancer-specific mRNA re-splicing in normal cells by knockdown of EJC core proteins, eIF4A3, MAGOH and Y14, implicating that the EJC core is a repressor of mRNA re-splicing. We conclude that the EJC core is a critical mRNA quality control factor to prevent extra re-splicing on mature mRNA.

Academic Significance and Societal Importance of the Research Achievements

スプライシングはmRNAが蛋白質合成の鋳型であるが故に、遺伝子発現での必須過程である。スプライシングが完了したmRNAが、なぜ再びスプライシングされないのか? という未解決問題の証明につながるブレークスルーが得られた。スプライシングが完了したmRNA上には、EJCが形成されることが知られ、EJCは、スプライシング後の核外輸送やNMDの機能に重要であることが知られているが、スプライシング完了のシグナルになっているかどうかは、まだ誰も証明していない。EJCが再スプライシングを抑制する事実の発見から、未知のスプライシング完了機構の解明につながると期待できる。もし成功すれば、教科書を書き換えるだろう。

Report

(5 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • Research Products

    (26 results)

All 2019 2018 2017 2016 Other

All Int'l Joint Research (3 results) Journal Article (4 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 3 results,  Open Access: 3 results) Presentation (15 results) (of which Int'l Joint Research: 9 results,  Invited: 1 results) Book (1 results) Remarks (3 results)

  • [Int'l Joint Research] 台湾大学病院耳鼻咽喉科(台湾)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] 台湾大学病院耳鼻咽喉科(台湾)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] University of Natural Resources/Dept. of Applied Genet. and Cell Biol.(オーストリア)

    • Related Report
      2017 Annual Research Report
  • [Journal Article] Component of splicing factor SF3b plays a key role in translational control of polyribosomes on the endoplasmic reticulum2019

    • Author(s)
      Ueno Tomonori、Taga Yuki、Yoshimoto Rei、Mayeda Akila、Hattori Shunji、Ogawa-Goto Kiyoko
    • Journal Title

      Proceedings of the National Academy of Sciences

      Volume: 116 Issue: 19 Pages: 9340-9349

    • DOI

      10.1073/pnas.1901742116

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A distinct subset of human short introns: U2AF heterodimer is replaced by SPF45 (RBM17) as general splicing factor2019

    • Author(s)
      K. Fukumura, R. Yoshimoto, T. Hirose, K. Inoue, A. Mayeda
    • Journal Title

      bioRxiv

      Volume: - Pages: 784868-784868

    • DOI

      10.1101/784868

    • Related Report
      2019 Annual Research Report
    • Open Access
  • [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 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] RNPS1 suppresses errors in pre-mRNA splicing: A key factor for mRNA quality control2018

    • Author(s)
      K. Fukumura, K. Inoue, A. Mayeda
    • Journal Title

      Biochem. Biophys. Res. Commun.

      Volume: 496 Issue: 3 Pages: 921-926

    • DOI

      10.1016/j.bbrc.2018.01.120

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Presentation] Repressors of cancer-specific mRNA re-splicing: Key factors for splicing fidelity or mRNA quality control?2019

    • Author(s)
      A. Mayeda
    • Organizer
      Annual Congress of Taiwan Society of Otorhinolaryngology Head and Neck Surgery/Taiwan Academy of Otology
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] EJC core represses cancer-specific mature mRNA re-splicing - EJC as a signal to terminate splicing2019

    • Author(s)
      T. Kameyama
    • Organizer
      Eukaryotic mRNA Processing Meeting
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] A distinct subset of human short introns with weak pyrimidine tract: U2AF heterodimer is replaced by SPF45/RBM17 as general splicing factor2019

    • Author(s)
      A. Mayeda
    • Organizer
      The 24th Annual Meeting of the RNA Society
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] EJC represses caner-specific mature mRNA re-splicing: EJC as a guardian to maintain the integrity of mRNA2019

    • Author(s)
      A. Mayeda
    • Organizer
      第42回 日本分子生物学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] The PSAP complex is a global guardian of pre-mRNA splicing fidelity.2018

    • Author(s)
      K. Fukumura, A. Mayeda
    • Organizer
      Gordon Research Conference: Post-Transcriptional Gene Regulation--Integrating Technology and Mechanisms to Illuminate Function in RNA Biology
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Identification of tumor suppressor RBM4a as a repressor of cancer-specific mature mRNA re-splicing.2018

    • Author(s)
      T. Kameyama
    • Organizer
      第77回 日本癌学会学術総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] EJCががん細胞特異的な成熟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働く新たなEJCの役割.2018

    • Author(s)
      大谷 雄太, 亀山 俊樹, 前田 明
    • Organizer
      第41回 日本分子生物学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] A repressor candidate of cancer specific mRNA re-splicing: A key factor for splicing fidelity or mRNA quality control?2017

    • Author(s)
      T. Kameyama, K. Fukumura, K. Inoue, T. Hirose, A. Mayeda
    • Organizer
      The 22nd Annual Meeting of the RNA Society
    • Place of Presentation
      Prague Congress Center (Czech Republic)
    • Year and Date
      2017-05-30
    • Related Report
      2016 Annual Research 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)
      T. Kameyama, K. Fukumura, K. Inoue, T. Hirose, A. Mayeda
    • Organizer
      2017 International Symposium on the 'Hallmarks of Cancer: Focus on RNA'
    • Place of Presentation
      Prague Congress Center (Czech Republic)
    • Year and Date
      2017-05-28
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] A repressor candidate of cancer specific mRNA re-splicing: a key factor for splicing fidelity or mRNA quality control2017

    • Author(s)
      T. Kameyama, K. Fumura, K. Inoue, T. Hirose, A. Mayeda
    • Organizer
      International Symposium on the Hallmarks of Cancer: Focus on RNA
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] A repressor candidate of cancer specific mRNA re-splicing: a key factor for splicing fidelity or mRNA quality control2017

    • Author(s)
      T. Kameyama, K. Fumura, K. Inoue, T. Hirose, A. Mayeda
    • Organizer
      The 22th Annual Meeting of the RNA Society
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 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 Annual Research 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, 福村 和宏, 井上 邦夫, 廣瀬 哲朗, 前田 明
    • Organizer
      2017年度 生命科学系学会合同年次大会
    • Related Report
      2017 Annual Research Report
  • [Presentation] ヒト遺伝子の「無意味」な配列の「意味」を考えてみよう!2016

    • Author(s)
      亀山 俊樹, 芳本 玲, 福村和宏, 嶋田誠, Maria Kalyna, 前田 明
    • Organizer
      第39回 日本分子生物学会年会
    • Place of Presentation
      パシフィコ横浜(神奈川県、横浜市)
    • Year and Date
      2016-11-30
    • Related Report
      2016 Annual Research Report
  • [Presentation] Cisplatin-stimulated cancer-specific mature mRNA re-splicing is under the control of tumor suppressor p532016

    • Author(s)
      T. Kameyama, Y. Amemoto, A. Mayeda
    • Organizer
      The 21st Annual Meeting of the RNA Society / The 18th Annual Meeting of the RNA Society of Japan
    • Place of Presentation
      京都国際会館(京都府、京都市)
    • Year and Date
      2016-06-28
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Book] 実験医学特集号「coding RNAルネッサンス」2016

    • Author(s)
      片岡 直行, 前田 明
    • Total Pages
      143
    • Publisher
      羊土社
    • Related Report
      2016 Annual Research 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 Annual Research Report
  • [Remarks] 藤田保健衛生大学 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/~gem-1/

    • Related Report
      2017 Annual Research Report
  • [Remarks] 藤田保健衛生大学 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/~gem-1/

    • Related Report
      2016 Annual Research Report

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Published: 2016-04-21   Modified: 2022-08-22  

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