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2008 Fiscal Year Annual Research Report

ΑΙDによる抗原刺激依存性抗体遺伝子改編機構の研究

Research Project

Project/Area Number 17002015
Research InstitutionKyoto University

Principal Investigator

本庶 佑  Kyoto University, 医学研究科, 客員教授 (80090504)

Keywords免役学 / 抗体 / クラススイッチ / ゲノム / 癌
Research Abstract

AIDがどのようにしてクラススイッチにおけるDNA切断を行なうかについて、新たな発見があった。すなわち、Topoisomerase 1がS領域およびV領域のDNA切断を行なう事を明らかにした。その根拠は、1.Topoisomeraseの特異的阻害剤であるカンプトテシンによってクラススイッチおよびS領域切断が阻害されること、2.AIDによってTopoisomeraseの翻訳が低下し、Topisomerase1の量が低下すること、3.RNAi法によってTopoisomerase1を低下させると、AIDの発現と同様にS領域の切断、クラススイッチが増強すること、4.逆にAIDによるクラススイッチがTopoisomerase1の増加によって減少することである。これらの発見は従来のDNA脱アミノ学説では説明できず、我々が唱えてきたRNA編集説を強くサポートするものである。また、AIDの発現異常によって発癌の危険性が指摘されているので、AIDのプロモータ解析を行ない、ここにおいてサプレッサーが重要な役割をしていることを明らかにした。AIDのプロモータとエンハンサの解析を行ない、イントロの中にサプレッサーが存在し、そのサプレッサーによりAIDが通常の状況では発現しないようになっていることを明らかにした。また、上流のエンハンサにサイトカイン、CD40、Toll receptor等のシグナルに反応してAIDを活性化させる領域を見いだした。これらの解析は様々なDNA断片の欠失やミューテーションを導入したルシフェレースアッセーによって行ない、これまで様々な部分的な解析からの推測によっていたAID発現制御の全貌を明らかにした。今後、この知見に基づき、in vivoでのAID発現制御と発癌の関係をさらに明らかにする予定である。

  • Research Products

    (41 results)

All 2010 2009 2008 Other

All Journal Article (23 results) (of which Peer Reviewed: 23 results) Presentation (16 results) Book (1 results) Remarks (1 results)

  • [Journal Article] B cell-specific and stimulation-responsive enhancers derepress the Aicda gene by overcoming the effects of silencers.2010

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

      Nature Immunol. 11

      Pages: 148-154

    • Peer Reviewed
  • [Journal Article] Author's reply : Apex2 is required for efficient somatic hypermutation but not for class switch recombination of immunoglobilin genes.2010

    • Author(s)
      Sabouri, Z., et al.
    • Journal Title

      Int.Immunol. 22

      Pages: 213-214

    • Peer Reviewed
  • [Journal Article] Anti-programmed cell death 1 antibody reduces CD4+PD-1+ T cells and relieves the lupus-like nephritis of NZB/W F1 mice.2010

    • Author(s)
      Kasagi, S., et al.
    • Journal Title

      J.Immunol. 184

      Pages: 2337-2347

    • Peer Reviewed
  • [Journal Article] Preventing AID, a physiological mutator, from deleterious activation : regulation of the genomic instability that is associated with antibody diversity. (Review)2010

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

      Int.Immunol. 22

      Pages: 227-235

    • Peer Reviewed
  • [Journal Article] A novel mouse model of hepatocarcinogenesis triggered by AID causing deleterious p53 mutations.2009

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

      Oncogene 28

      Pages: 469-478

    • Peer Reviewed
  • [Journal Article] Forebrain ependymal cell are Notch-dependent and generate neuroblasts and astrocytes after stroke.2009

    • Author(s)
      Carlen, M., et al.
    • Journal Title

      Nat.Neurosci. 12

      Pages: 259-267

    • Peer Reviewed
  • [Journal Article] Carboxy-terminal domain of AID required for its mRNA complex formation in vivo.2009

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

      Proc.Natl.Acad.Sci.USA 106

      Pages: 2747-2751

    • Peer Reviewed
  • [Journal Article] Further evidence for involvement of a non-canonical function of uracil DNA glycosylase in class switch recombination.2009

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

      Proc.Natl.Acad.Sci.USA 106

      Pages: 2752-2757

    • Peer Reviewed
  • [Journal Article] The C-terminal region of AID is responsible for a novel function other than DNA cleavage in class switch recombination.2009

    • Author(s)
      Doi, M., et al.
    • Journal Title

      Proc.Natl.Acad.Sci.USA 106

      Pages: 2758-2763

    • Peer Reviewed
  • [Journal Article] Molecular mechanism for generation of antibody memory.2009

    • Author(s)
      Shivarov, V., et al.
    • Journal Title

      Phil.Trans.R.Soc.Lond. 364

      Pages: 569-575

    • Peer Reviewed
  • [Journal Article] Preferential generation of follicular B helper T (TFH) cells from Foxp3+ T cells in gut Peyer's patches.2009

    • Author(s)
      Tsuji, M., et al.
    • Journal Title

      Science 323

      Pages: 1488-1493

    • Peer Reviewed
  • [Journal Article] Identification of QTLs that modify peripheral neuropathy in NOD. H2^b-Pdcd^<-/-> mice.2009

    • Author(s)
      Jiang, F., et al.
    • Journal Title

      Int.Immunol. 21

      Pages: 499-509

    • Peer Reviewed
  • [Journal Article] Cytokine-producing effector B cells regulate type 2 immunity to H.polygyrus.2009

    • Author(s)
      Wojciechowski, W., et al.
    • Journal Title

      Immunity 30

      Pages: 421-433

    • Peer Reviewed
  • [Journal Article] Apex2 is required for efficient somatic hypermutation but not for class switch recombination of immunoglobilin genes.2009

    • Author(s)
      Sabouri, Z., et al.
    • Journal Title

      Int.Immunol. 21

      Pages: 947-955

    • Peer Reviewed
  • [Journal Article] RBP-J promotes neuronal differentiation and inhibits oligodendroglial development in adult neurogenesis.2009

    • Author(s)
      Fujimoto, M., et al.
    • Journal Title

      Developmental Biology 332

      Pages: 339-350

    • Peer Reviewed
  • [Journal Article] AID-induced decrease in topoisomerase 1 induces DNA structural alteration and DNA cleavage for class switch recombination.2009

    • Author(s)
      Kobayashi, M., et al.
    • Journal Title

      Proc.Natl.Acad.Sci.USA 106

      Pages: 22375-22380

    • Peer Reviewed
  • [Journal Article] AID is required for germinal center-derived lymphomagenesis.2008

    • Author(s)
      Pasqualucci, L., et al.
    • Journal Title

      Nat.Genet. 40

      Pages: 108-112

    • Peer Reviewed
  • [Journal Article] A memoir of AID, which engraves antibody memory on DNA.2008

    • Author(s)
      Honjo, T.
    • Journal Title

      Nature Immunol. 9

      Pages: 335-337

    • Peer Reviewed
  • [Journal Article] Dissociation of in vitro DNA deamination activity and physiological functions of AID mutants.2008

    • Author(s)
      Shivarov, V., et al.
    • Journal Title

      Proc.Natl.Acad.Sci.USA. 105

      Pages: 15866-15871

    • Peer Reviewed
  • [Journal Article] Loss of intestinal crypt progenitor cells owing to inactivation of both Notch1 and Notch2 is accompanied by derepression of CDKinhibitors p27^<Kip1> and p57^<Kip2>.2008

    • Author(s)
      Riccio, O., et al.
    • Journal Title

      EMBO Rep. 9

      Pages: 377-383

    • Peer Reviewed
  • [Journal Article] The programmed death-1 and interleukin-10 pathways play a down-modulatory role in LP-BM5 retrovirus-induced murine immunodeficiency syndrome.2008

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

      J.Virol. 82

      Pages: 2456-2469

    • Peer Reviewed
  • [Journal Article] Activation-induced cytidine deaminase links between inflammation and the development of colitis-associated colorectal cancers.2008

    • Author(s)
      Endo, Y., et al.
    • Journal Title

      Gastroenterology. 135

      Pages: 889-898

    • Peer Reviewed
  • [Journal Article] Organ-specific Profiles of Genetic Chances in Cancers Caused by Activation-induced Cytidine Deaminase Expression.2008

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

      Int.J.Cancer 123

      Pages: 2735-2740

    • Peer Reviewed
  • [Presentation] AID-mediated antibody memory generation and genomic instability2010

    • Author(s)
      本庶佑
    • Organizer
      The 18th Symposium on Recent Advances in Cellular and Molecular Biology細胞及び分子生物学学会
    • Place of Presentation
      Taipei, Taiwan
    • Year and Date
      2010-01-21
  • [Presentation] AID-induced decrease in topoisomerase 1 induces DNA structural alteration and DNA cleavage for class switch recombination.2009

    • Author(s)
      本庶佑
    • Organizer
      Seminar at NIMR, MRC
    • Place of Presentation
      London, UK
    • Year and Date
      2009-12-03
  • [Presentation] 抗体記憶をゲノムに刻むAID2009

    • Author(s)
      本庶佑
    • Organizer
      第59回日本アレルギー学会
    • Place of Presentation
      Akita, Japan
    • Year and Date
      2009-10-31
  • [Presentation] ワクチンによる抗体記憶形成のメカニズム、またはMolecular mechanism of generation of antibody memory by vaccination2009

    • Author(s)
      本庶佑
    • Organizer
      日本消化器病学会
    • Place of Presentation
      Kyoto, Japan
    • Year and Date
      2009-10-16
  • [Presentation] Involvement of topoisomerase 1 in AID-mediated antibody memory generation and genomic instability2009

    • Author(s)
      本庶佑
    • Organizer
      The Annual Meeting of the Korean Society for Molecular and Cellular Biology
    • Place of Presentation
      Seoul, Korea
    • Year and Date
      2009-10-15
  • [Presentation] AID as the engraver of antibody memory and inducer of genome instability2009

    • Author(s)
      本庶佑
    • Organizer
      The First International Kishimoto Foundation Symposium : "Immune Regulation : Present and Future"
    • Place of Presentation
      Osaka, Japan
    • Year and Date
      2009-05-25
  • [Presentation] The molecular mechanism for generation of antibody memory2009

    • Author(s)
      本庶佑
    • Organizer
      The 2009 Keystone Symposium on Human Immunology and Immunodeficiencies
    • Place of Presentation
      Beijing, China
    • Year and Date
      2009-05-13
  • [Presentation] Molecular studies on generation of antibody memory2009

    • Author(s)
      本庶佑
    • Organizer
      The International Symposium on Genomics and Medicine, The Fondation Jean Dausset-Centre d'Etude du Polymorphisme Humain (CEPH)
    • Place of Presentation
      Paris, France
    • Year and Date
      2009-03-23
  • [Presentation] Molecular mechanism for generation of antibody memory2008

    • Author(s)
      本庶佑
    • Organizer
      第38回日本免疫学会学術集会
    • Place of Presentation
      Kyoto, Japan
    • Year and Date
      2008-12-01
  • [Presentation] ゲノムに刻む抗体記憶/AID, the engraver of antibody memory2008

    • Author(s)
      本庶佑
    • Organizer
      Japan-German Immunology Seminar 2008 : Immune Regulation in Health and Disease
    • Place of Presentation
      Fukuoka, Japan
    • Year and Date
      2008-11-04
  • [Presentation] Molecular mechanism for generation of antibody memory2008

    • Author(s)
      本庶佑
    • Organizer
      FIMSA 2008
    • Place of Presentation
      Taipei, Taiwan
    • Year and Date
      2008-10-17
  • [Presentation] Molecular mechanism for generation of antibody memory2008

    • Author(s)
      本庶佑
    • Organizer
      2008 Leskowitz Memorial Lecture at Tufts University School of Medicine
    • Place of Presentation
      Boston, USA
    • Year and Date
      2008-09-26
  • [Presentation] Dissociation of in vitro DNA deamination activity and physiological functions by AID mutants2008

    • Author(s)
      本庶佑
    • Organizer
      Workshop on AUD Biology and Disease
    • Place of Presentation
      North Carolina, USA
    • Year and Date
      2008-09-23
  • [Presentation] AID, the engraver of antibody memory2008

    • Author(s)
      本庶佑
    • Organizer
      Seminar at Seoul National University
    • Place of Presentation
      Seoul, Korea
    • Year and Date
      2008-07-18
  • [Presentation] Dissociation of in vitro DNA deamination activity and physiological functions by AID mutants2008

    • Author(s)
      本庶佑
    • Organizer
      The Royal Society Discussion Meeting on DNA deamination in immunity, virology, and cancer
    • Place of Presentation
      London, UK
    • Year and Date
      2008-06-09
  • [Presentation] Somatic hypermutation and class switch recombination2008

    • Author(s)
      本庶佑
    • Organizer
      The International Ataxia-Telangiectasia Workshop 2008
    • Place of Presentation
      Shiga, Japan
    • Year and Date
      2008-04-26
  • [Book] いのちとはなにか-幸福・ゲノム・病2009

    • Author(s)
      本庶佑
    • Total Pages
      154
    • Publisher
      岩波書店
  • [Remarks]

    • URL

      http://www2.mfour.med.kyoto-u.ac.jp/

URL: 

Published: 2011-06-16   Modified: 2016-04-21  

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