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Elucidation of a novel mechanism for regulation of signal transduction through Insulin receptor alternative splicing

Research Project

Project/Area Number 18K06012
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 42030:Animal life science-related
Research InstitutionThe University of Tokyo

Principal Investigator

Kataoka Naoyuki  東京大学, 大学院農学生命科学研究科(農学部), 准教授 (60346062)

Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywordsインスリン受容体 / 選択的スプライシング / Rbfox2 / SRSF3 / ISE / ESE / シグナル伝達 / アミノ酸 / スプライシングレポーター / スプライシングバリアント / IRS-1 / IRsome
Outline of Final Research Achievements

Insulin receptor (IR) pre-mRNA undergoes alternative splicing to produce two isoforms, IR-A and B. We prepared a splicing reporter that contains a portion of rat IR gene. We confirmed our reporter recapitulate endogenous IR splicing pattern in rat H4IIE cells, and deletion analyses identified a binding site for splicing regulator Rbfox. We further demonstrate that SRSF3 and Rbfox2 are required for IR-B type splicing in H4IIE cells. Finally, we found that amino acid depletion causes IR splicing change, indicating that amino acid has a novel role as a metabolic regulatory signal.

Academic Significance and Societal Importance of the Research Achievements

インスリン受容体のアイソフォームの一つIR-AはIGF-IIにも結合し、がんの増殖を助ける役割があると考えられる。インスリン様活性は、その制御が崩れた場合、インスリン抵抗性や糖尿病、がんや低成長といった疾患となる。実際にアミノ酸バランスを変化させて餌を給餌したラット成体肝では、IR-A型が増えるのが観察されている。IR-B型を産生するための機構が明らかになったことで、アミノ酸飢餓によりIR-A型に変化する機構の糸口がつかめた。今後その機構を解明し、IR-A型に変化した肝臓でIR-B型へと戻す方法を探索することで、インスリン様活性の異常に起因するがんや糖尿病、脂肪肝の治療に貢献できる。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (11 results)

All 2020 2019 Other

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

  • [Journal Article] RNA binding activity of HSV-2 ICP27 protein2020

    • Author(s)
      Kawamura Hidenobu、 Nojima Takayuki、 Oshiro-Ideue Takako、Kataoka Naoyuki* and Hagiwara Masatoshi*(*Corresponding authors)
    • Journal Title

      RNA & DISEASE

      Volume: 7

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The cysteine residue at 424th of pyruvate kinase M2 is crucial for tetramerization and responsiveness to oxidative stress2020

    • Author(s)
      Masaki So、Hashimoto Kozue、Kihara Daiki、Tsuzuki Chizuru、Kataoka Naoyuki、Suzuki Kenji
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 526 Issue: 4 Pages: 973-977

    • DOI

      10.1016/j.bbrc.2020.03.182

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Rbm38 Reduces the Transcription Elongation Defect of the SMEK2 Gene Caused by Splicing Deficiency2020

    • Author(s)
      Muraoka Shintaro、Fukumura Kazuhiro、Hayashi Megumi、Kataoka Naoyuki、Mayeda Akila、Kaida Daisuke
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 21 Issue: 22 Pages: 8799-8799

    • DOI

      10.3390/ijms21228799

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Multiple nuclear localization sequences in SRSF4 protein2020

    • Author(s)
      Masaki So、Kabuto Takafumi、Suzuki Kenji、Kataoka Naoyuki
    • Journal Title

      Genes to Cells

      Volume: 25 Issue: 5 Pages: 327-333

    • DOI

      10.1111/gtc.12756

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Myelodysplastic Syndrome-Associated SRSF2 Mutations Cause Splicing Changes by Altering Binding Motif Sequences2019

    • Author(s)
      Masaki So、Ikeda Shun、Hata Asuka、Shiozawa Yusuke、Kon Ayana、Ogawa Seishi、Suzuki Kenji、Hakuno Fumihiko、Takahashi Shin-Ichiro、Kataoka Naoyuki
    • Journal Title

      Frontiers in Genetics

      Volume: 10 Pages: 1-8

    • DOI

      10.3389/fgene.2019.00338

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Uncovering a mechanism for MDS onset caused by mis-splicing2020

    • Author(s)
      片岡直行、正木聡
    • Organizer
      第43回日本分子生物学会年会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Mechanism for hypoxia-response through alternative splicing regulation2019

    • Author(s)
      片岡 直行、伊藤 美佳子、増田 章男、大野 欽司、江口 加代子、伯野 史彦、 高橋 伸一郎、中山 恒
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Research-status Report
  • [Presentation] 低酸素条件下における選択的スプライシング機構の解明2019

    • Author(s)
      片岡 直行、伊藤 美佳子、増田 章男、大野 欽司、江口 加代子、伯野 史彦、 高橋 伸一郎、中山 恒
    • Organizer
      第21回日本RNA学会年会
    • Related Report
      2019 Research-status Report
  • [Presentation] Rbfox2 protein mediates exon 11 inclusion in insulin receptor alternative splicing in hepatoma cells2019

    • Author(s)
      Naoyuki Kataoka
    • Organizer
      Gordon Research Conference IGF and Insulin System in Physiology and Disease
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Book] Applied RNA Bioscience (Editors: Seiji Masuda, Shingo Izawa)2019

    • Author(s)
      Naoyuki Kataoka
    • Total Pages
      286
    • Publisher
      Springer Nature
    • Related Report
      2019 Research-status Report
  • [Remarks] 東京大学 大学院農学生命科学研究科 細胞生化学研究室 HP

    • URL

      http://www.vm.a.u-tokyo.ac.jp/seika/index.html

    • Related Report
      2020 Annual Research Report

URL: 

Published: 2018-04-23   Modified: 2022-01-27  

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