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ノックアウトマウスを用いた基本転写伸長因子の生理機能の解明

Research Project

Project/Area Number 15770107
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeSingle-year Grants
Research Field Molecular biology
Research InstitutionTokyo Institute of Technology

Principal Investigator

山口 雄輝  東京工業大学, 大学院・生命理工学研究科, 助手 (50345360)

Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2004: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2003: ¥1,600,000 (Direct Cost: ¥1,600,000)
Keywords転写伸長因子 / NELF / ノックアウトマウス / 胎性致死
Research Abstract

NELFはRNAポリメラーゼIIによる転写伸長を抑制することが知られる唯一の因子である.NELFの個体レベルでの機能を明らかにするため,NELFの4つのサブユニットのうち2つの遺伝子を破壊したマウスを作製した.NELF-E欠損マウスは一見正常に誕生し生育した.一方,NELF-A欠損マウスはE10.5以前で耐性致死となった.よく調べたところ,NELF-E欠損マウスはNELF-EのC末端側の約2/3を欠損したトランケート型タンパク質を発現していた.このC末端部分には,機能的に重要と考えていたRNA結合ドメインRRMが含まれる.NELF-Eの欠損がnullでないため断定はできないものの,以上の結果は,個体レベルでの生存に関してNELFの2つのサブユニットが対照的な要求性を示すという予想外の可能性を示した.NELF-A欠損マウスについて詳しく調べたところ,E8.5の段階で-/-変異体がメンデル律に則って見つかった.ただし,それらは一見するとE6.5に相当するような小さな胚(あるいは吸収途中と思われる残骸組織)であり,組織学的解析もそれを裏付けた.in situハイブリダイゼーションの結果によれば,NELF-Aは少なくともE8.5以降の段階で様々な組織に発現していた.以上の結果はNELFの要求性が極めて発生段階特異的に現れることを示しており,大変興味深い.そもそもNELFは転写を普遍的に制御する因子として我々が同定した.初期発生の過程で転写は2細胞期から始まっているわけだが,NELF-Aがなくても着床(E4.5)まで問題なく進み,E6.5あたりで突如として発達遅滞が引き起こされるという今回の結果は,我々にとって意外であり,NELFの遺伝子特異的な働きを明確に示すものと考えている.

Report

(2 results)
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • Research Products

    (13 results)

All 2005 2004 Other

All Journal Article (6 results) Book (1 results) Publications (6 results)

  • [Journal Article] NF-Y is essential for the recruitment of RNA polymerase II and inducible transcription of several CCAAT box-containing genes2005

    • Author(s)
      Kabe et al.
    • Journal Title

      Molecular and Cellular Biology 25・1

      Pages: 512-522

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Molecular characterization of Drosophila NELF2005

    • Author(s)
      Chwen-Huey et al.
    • Journal Title

      Nucleic Acids Research 33・4

      Pages: 1269-1279

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Mediator requirement for both recruitment and post-recruitment steps in transcription initiation2005

    • Author(s)
      Wang et al.
    • Journal Title

      Molecular Cell 17・5

      Pages: 683-694

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Interferon regulatory factor 1 (IRF-1) and IRF-2 distinctively up-regulate gene expression and production of interleukin-7 in human intestinal epithelial cells2004

    • Author(s)
      Oshima et al.
    • Journal Title

      Molecular and Cellular Biology 24・14

      Pages: 6298-6310

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Attenuation of estrogen receptor α-mediated transcription through estrogen-stimulated recruitment of a negative elongation factor2004

    • Author(s)
      Aiyar et al.
    • Journal Title

      Genes and Development 18・17

      Pages: 2134-2146

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Locus-specific requirements for Spt5 in transcriptional activation and repression in Drosophila2004

    • Author(s)
      Jennings et al.
    • Journal Title

      Current Biology 14・18

      Pages: 1680-1684

    • Related Report
      2004 Annual Research Report
  • [Book] キーワードで理解する転写イラストマップ2004

    • Author(s)
      山口 雄輝(分担)
    • Total Pages
      204
    • Publisher
      羊土社
    • Related Report
      2004 Annual Research Report
  • [Publications] Narita et al.: "Human transcription elongation factor NELF : Identification of novel subunits and reconstitution of the functionally active complex"Molecular and Cellular Biology. 23・6. 1863-1873 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Nedialkov et al.: "NTP-driven translocation by human RNA polymerase II"Journal of Biological Chemistry. 278・20. 18303-18312 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Wu et al.: "NELF and DSIF cause promoter proximal pausing on the hsp70 promoter in Drosophila"Genes and Development. 17・11. 1402-1414 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Inukai et al.: "A novel hydrogen peroxide-induced phosphorylation and ubiquitination pathway leading to RNA polymerase II proteolysis"Journal of Biological Chemistry. (in press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ainbinder et al.: "Elongation inhibition by DSIF is regulated by the A20 promoter via a novel negative element and NF-κB"Molecular and Cellular Biology. (in press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Endou et al.: "Human Spt6 stimulates transcription elongation by RNA polymerase II in vitro"Molecular and Cellular Biology. (in press). (2004)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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