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pVHLリガーゼによる環境応答

Research Project

Project/Area Number 12146202
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionOsaka City University (2001-2004)
Kyoto University (2000)

Principal Investigator

岩井 一宏  大阪市立大学, 大学院医学研究科, 教授 (60252459)

Project Period (FY) 2000 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥34,100,000 (Direct Cost: ¥34,100,000)
Fiscal Year 2004: ¥8,500,000 (Direct Cost: ¥8,500,000)
Fiscal Year 2003: ¥8,600,000 (Direct Cost: ¥8,600,000)
Fiscal Year 2002: ¥8,500,000 (Direct Cost: ¥8,500,000)
Fiscal Year 2001: ¥8,500,000 (Direct Cost: ¥8,500,000)
Keywordsストレス / 環境 / ユビキチン修飾 / VHL / 選択的蛋白分解 / pVHLリガーゼ / 腎細胞癌 / PKCλ / IRP2 / ユビキチン / 酸化修飾 / HIF-1 / プロテアソーム
Research Abstract

von Hippel-Lindau(VHL)病の原因遺伝子として同定されたVHLは80%以上の腎細胞癌においても欠損しているがん抑制性遺伝子である。その産物であるpVHLはelongin B、elongin C(VBC複合体)との結合を介してCul2と結合し、pVHLリガーゼ複合体を形成しており、pVHLはその基質認識サブユニットとして機能する。また、Cul2のユビキチン様蛋白質NEDD8による修飾がpVHLリガーゼの活性制御に必須である。pVHLリガーゼの活性中心であるRINGフィンガー蛋白質:Rbxlは、Cul2のNEDD8化、基質のユビキチン化活性を制御しているが、その機能メカニズムには不明な点が多い。そこで本年度はRbx1の変異体を作成することにより、Rbx1のCul2のNEDD8化、基質のユビキチン化制御メカニズムについて検討を加えた。その結果、基質のユビキチン化のみを選択的に抑制する、あるいはCul2のNEDD8化を選択的に抑制する変異体を見いだしたことから、RbxlはNEDD8とユビキチンのE2両者と結合してそれらモディファイヤーによる修飾を触媒すること、それらE2とRbxlの異なった部位で結合していることが明らかとなった。
本研究のもう1つのテーマである鉄代謝の制御因子IRP2の鉄依存性ユビキチン化に関してはIRP2のヘム依存性分解メカニズムに関して解析を進め、IRP2特異的なIDD (iron-dependent degradation)ドメインに存在するheme-regulatory motif (HRM)がヘム結合部位であり、その周囲のアミノ酸残基を酸化することによりHOIL-1ユビキチンリガーゼで識別されユビキチン化されることを明らかにした。(投稿中)

Report

(5 results)
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • 2000 Annual Research Report
  • Research Products

    (30 results)

All 2005 2004 Other

All Journal Article (6 results) Publications (24 results)

  • [Journal Article] 2004年度 ノーベル化学賞 ユビキチン依存性タンパク質分解幾構の発見2005

    • Author(s)
      岩井 一宏
    • Journal Title

      現代化学 406

      Pages: 31-34

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Genetic ablations of iron regulatory proteins 1 and 2 reveal why iron reulatory protein 2 dominates iron homeostasis.2004

    • Author(s)
      Meyron-Holtz, E., G., et al.
    • Journal Title

      EMBO J. 23

      Pages: 386-395

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Structural basis of sugar-recognizing ubiquitin ligase.2004

    • Author(s)
      Mizushima, T., et al.
    • Journal Title

      Nat. Struct. Mol. Biol. 11

    • Related Report
      2004 Annual Research Report
  • [Journal Article] The Ubiquitin System: From Basic Mechanisms to the Patient Bed.2004

    • Author(s)
      Ciechanover, A, et al.
    • Journal Title

      IUBMB Life 56

      Pages: 193-201

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Association of HPV infbction with prognosis after neoadjuvant che motherapy in advanced uterine cervical cancer.2004

    • Author(s)
      Nobeyama, H., et al.
    • Journal Title

      Int. J. Mol. Med. 14

      Pages: 101-105

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Structural basis for distinct roles of Lys63- and Lys48-linked polyubiquitin chains.2004

    • Author(s)
      Tenno, T., et al.
    • Journal Title

      Genes Cells. 9

      Pages: 865-875

    • Related Report
      2004 Annual Research Report
  • [Publications] Yamanaka, K., et al.: "Identification of the ubiquitin-protein ligase that recognizes oxidized IRP2"Nature Cell Biology. 5. 336-340 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ishida, D., et al.: "Myeloproliferative stem cell disorders by deregulated Rap1 activation in SPA-1-deficient mice."Cancer Cell. 4. 55-65 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Iwai K: "An ubiquitin ligase recognizing a protein oxidized by iron : implications for the turnover of oxidatively damaged proteins"J.Biochem.. 134. 175-182 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yoshida, Y., et al.: "Fbs2 is a new member of the E3 ubiquitin ligase family that recognizes sugar chains."J Biol Chem.. 278. 43877-43884 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Meyron-Holtz EG, et al.: "Genetic ablations of iron regulatory proteins 1 and 2 reveal why iron regulatory protein 2 dominates iron homeostasis"EMBO J.. 23. 386-395 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Mizushima, T et al.: "Structural basis of sugar-recognizing ubiquitin ligase"Nature Structural & Molecular Biology. (In press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yamanaka, K. et al.: "Identification of the ubiquitin-protein ligase that recognizes oxidized IRP2. In press"Nature Cell Biology. (In Press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ashizuka, M. et al.: "A novel translational control through Iron-Responsive Element by interaction of multifunctional protein YB-1 and IRP2"Molecular Cell Biology. 22. 6375-6383 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yoshida, Y. et al.: "E3 ubiquitin-ligase that recognises sugar chains"Nature. 418. 438-442 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Amir, R.E.et al.: "The NEDD8 pathway is essential for SCF-beta-TrCP -mediated ubiquitination and processing of the NF-kB precursor p105"Journal of Biological Chemistry. 277. 23253-23259 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Sasaki, A. et al.: "A RING finger protein praja1 regulates Dlx5-dependent transcription through its ubiquitin ligase activity for the Dlx/Msx-interacting MAGE/Necdin family protein, Dlxin-1"Journal of Biological Chemistry. 277. 22541-22546 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 岩井 一宏, 恵 謙: "pVHLユビキチンリガーゼとその基質認識メカニズム"医薬ジャーナル 臨時増刊号 Medical Front Line ユビキチン代謝系の破綻と疾病 -癌・免疫病から神経病まで-. 38. 34-39 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] LaVaute, T., et al.: "Targeted deletion of iron regulatory protein 2 causes iron overload and neurodegenerative disease in mice"Nature Genet.. 27. 209-214 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Ciechanover, A., et al.: "Mechanisms of ubiquitin-mediated,limited processing of the NF-kappaB1 precursor protein p105"Biochimie. 83. 341-349 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kawakami, T., et al.: "NEDD8 recruits E2-ubiquitin to SCF E3 ligase"EMBO J.. 20. 4003-4012 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Okuda, H., et al.: "The Von Hippel-Lindau (VHL) Tumor Suppressor Protein mediates Ubiquitination of Activated Atypical Protein Kinase C"J.Biol.Chem.. 276. 43611-43617 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 岩井 一宏, 齋藤 耕二朗: "pVHLユビキチンリガーゼと発癌"実験医学・増刊号 タンパク質分解の最前線. 19. 44-49 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 山中 宏二, 岩井 一宏: "鉄イオン代謝制御蛋白IRP2の活性制御メカニズム"別冊・医学のあゆみ 酸化ストレス フリーラジカル医学生物学の最前線. 65-68 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] LaVaute,T., et al.: "Targeted deletion of iron regulatory protein 2 causes iron overload and neurodegenerative disease in mice."Nature Genet.. 27. 209-214 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kamura,T., et al: "Activation of HIFlalpha ubiquitination by a reconstituted von Hippel-Lindau (VHL) tumor suppressor complex."Proc.Natl.Acad.Sci.USA.. 97. 10430-10435 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Shimura,H. et al.: "Familial Parkinson's disease gene product, Parkin, is a ubiquitin-protein ligase."Nature Genet.. 25. 302-305 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Orian,A., et al.,: "SCFbeta-TrCP ubiquitin ligase-mediated processing of NF-kB p105 requires phosphorylation of its C-terminus by IkB kinase."EMBO J.. 19. 2580-2591 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Sadot,E., et al.: "Differential interaction of plakoglobin and beta-catenin with the ubiquitin-proteasome system."Oncogene. 19. 1992-2001 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 岩井一宏 他: "pVHLユビキチンリガーゼと発癌"実験医学・増刊号,タンパク質分解の最前線. 19. 142-147 (2001)

    • Related Report
      2000 Annual Research Report

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Published: 2001-04-01   Modified: 2018-03-28  

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