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ユビキチンリガーゼCdc4/Fbw7変異にともなう組織特異的細胞増殖機構の解明

Research Project

Project/Area Number 18013005
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionTohoku University

Principal Investigator

中山 啓子  Tohoku University, 大学院・医学研究科, 教授 (60294972)

Co-Investigator(Kenkyū-buntansha) 松本 雅記  九州大学, 生体防御医学研究所, 助手 (60380531)
Project Period (FY) 2006 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥14,600,000 (Direct Cost: ¥14,600,000)
Fiscal Year 2007: ¥7,400,000 (Direct Cost: ¥7,400,000)
Fiscal Year 2006: ¥7,200,000 (Direct Cost: ¥7,200,000)
Keywordsユビキチン / コンディショナルノックアウト / Cdc4 / Fbw7 / Notch / 細胞増殖 / Nocth / c-Myc / ノックアウトマウス
Research Abstract

ユビキチンリガーゼCdc4/Fbw7は、Notch、サイクリンE、c-Mycなど細胞増殖を促進する分子をユビキチン化するリガーゼであることが、試験管内の研究で明らかとなっている。また、様々ながんでCdc4/Fbw7の変異が報告されがん抑制遺伝子であると考えられる。すなわちCdc4/Fbw7の機能不全によりその基質分子が異常に蓄積し、そのために異常な細胞増殖、がん化を引き起こしていると考えられる。
そこでわれわれは、Cdc4/Fbw7のコンディショナルノックアウトマウスを作製し、Cdc4/Fbw7の生物学的な機能、特に発がんに対する関与を調べた。
まず、胎仔線維芽細胞でCdc4/Fbw7遺伝子を欠失させた。すると予想に反して細胞の増殖が著しく抑制された。これは、細胞周期のG1期での停止とアポトーシスの増加によるものであった。その際に、タンパク質の発現量を調べてみると、Cdc4/Fbw7の基質と報告されているもののうち、Notch-1が異常な蓄積を示すものの、サイクリンEやc-Mycの蓄積は認められなかった。そこで、Notch-1が転写因子として機能する際の共役因子であるRBP-jとのダブルノックアウトを作製しNotch-1の過剰な機能発現をキャンセルすることを試みた。すると、Cdc4/Fbw7シングルノックアウトで観察された増殖抑制は解除された。このことから、Cdc4/Fbw7は胎仔線維芽細胞においては、Nocthのシグナル量を制御することによって適切な増殖能力を維持していること考えられた。

Report

(2 results)
  • 2007 Annual Research Report
  • 2006 Annual Research Report
  • Research Products

    (36 results)

All 2008 2007 2006

All Journal Article (30 results) (of which Peer Reviewed: 14 results) Presentation (6 results)

  • [Journal Article] SCF型ユビキチンリガーゼによる細胞周期制御と発癌2008

    • Author(s)
      中山敬一and中山啓子
    • Journal Title

      実験医学(増刊) 26

      Pages: 46-54

    • Related Report
      2007 Annual Research Report
  • [Journal Article] SCFbeta TRCP1 activates and ubiquitylates TAp63 gamma2007

    • Author(s)
      J. R. Gallegos, et. al.
    • Journal Title

      J Biol Chem 283

      Pages: 66-75

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Essential role of Skp2-mediated p27 degradation in growth and adaptive expansion of pancreatic beta cells2007

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

      J Clin Invest 117

      Pages: 2869-2876

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Ablation of p27 enhance kainate-induced seizure and hippocampal Degeneration2007

    • Author(s)
      C. Ueyama, et. al.
    • Journal Title

      Neuroreport 18

      Pages: 1781-1785

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Conditional inactivation of Fbxw7 impairs cell-cycle exit during T cell differentiation and results in Iymphomatogenesis2007

    • Author(s)
      I. Onoyama, et. al.
    • Journal Title

      J Exp Med 204

      Pages: 2875-2888

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] nPKC {varepsilon}, a P2Y2-R downstream effector in regulated mucin secretion from airway goblet cells2007

    • Author(s)
      C. Ehre, et. al.
    • Journal Title

      Am J Physiol Cell Physiol 293

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Protein kinase C-delta phosphorylates Ebp1 and prevents its proteolytic degradation, enhancing cell survival2007

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

      J Neurochem 100

      Pages: 1278-1288

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Negative Feedback Loop in Bim-Caspase-3 Axis Regulating Apoptosis and Activity of Osteoclasts2007

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

      J Bone Miner Res 22

      Pages: 1631-1639

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The F Box Protein S Phase Kinase-associalted Protein 2 Regulates Adipose Mass and Adipocyte Number in Vion2007

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

      Obesity (Silver Spring) 15

      Pages: 1400-1408

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Cyclin D2 Translocates p27 out of the Nucleus and Promotes lts Degradation at the GO-G1 Transition2007

    • Author(s)
      E. Susaki, et. al.
    • Journal Title

      Mol Cell Biol 27

      Pages: 4626-4640

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Skp2 controls adipocyte proliferation during the development ofobesity2007

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

      J Biol Chem 282

      Pages: 2038-2046

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The cyclin-dependent kinase inhibitors p57 and p27 regulate neuronal migration in the developing mouse necortex2007

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

      J Biol chem 282

      Pages: 390-396

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Noncanonical Wnt signaling through G protein-linked PKCdelta activation promotes bone formation2007

    • Author(s)
      X. Tu, et. al.
    • Journal Title

      Dev Cell 12

      Pages: 113-127

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Asbestos-induced peribronchiolar cell proliferation and cytokine prodc-tion are attenuated in lungs of protein kinase C-delta knockout mice2007

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

      Am J Pathol 170

      Pages: 140-151

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Renal damage in obstructive nephropathy is decreased in Skp2-deficient mice2007

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

      Am J Pathol 171

      Pages: 473-483

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] PKC-delta plays non-redundant role in insulin secretion in pancreatic beta cell.2007

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

      J. Biol. Chem. 282

      Pages: 2707-2716

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Asbestos-induced peribronchiolar cell proliferation and cytoKine production are attenuated in lungs of protein kinase C-{delta} knockout mice.2007

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

      Am. J. Pathol. 170

      Pages: 140-151

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Noncanonical Wnt signaling through G protein-linked PKCdelta activation promotes bone formation.2007

    • Author(s)
      Tu, X.et al.
    • Journal Title

      Dev. Cell 12

      Pages: 113-127

    • Related Report
      2006 Annual Research Report
  • [Journal Article] The cyclin-dependent kinase inhibitors p57 and p27 regulate neuronal migration in the developing mouse neocortex.2007

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

      J. Biol. Chem. 282

      Pages: 390-396

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Skp2 controls adipocyte proliferation during the development of obesity.2007

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

      J. Biol. Chem. 282

      Pages: 2038-2046

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Suppression of centrosome amplification after DNA damage depends on p27 accumulation.2006

    • Author(s)
      Sugihara, E. et al.
    • Journal Title

      Cancer Res. 66

      Pages: 4020-4029

    • Related Report
      2006 Annual Research Report
  • [Journal Article] PKCdelta is necessary for Smad3 expression and transforming growth factor beta-induced fibronectin synthesis in vascular smooth muscle cells.2006

    • Author(s)
      Ryer, E.J.et al.
    • Journal Title

      Arterioscler. Thromb. Vasc. Biol. 26

      Pages: 780-786

    • Related Report
      2006 Annual Research Report
  • [Journal Article] HSP27 favors ubiquitination and proteasomal degradation of p27Kip1 and helps S-phase re-entry in stressed cells.2006

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

      FASEB J. 20

      Pages: 1179-1181

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Impaired germ cell development due to compromised cell cycle progression in Skp2-deficient mice.2006

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

      Cell Div. 1

      Pages: 4-4

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Transcriptional up-regulation of MMP12 and MMP13 by asbestos occurs via a PKCdelta-dependent pathway in murine lung.2006

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

      FASEB J. 20

      Pages: 997-999

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Geminin is essential for the development of preimplantation mouse embryos.2006

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

      Genes Cells 11

      Pages: 1281-1293

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Mitogenic signalling and the p16lNK4a-Rb pathway cooperate to enforce irreversible cellular senescence.2006

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

      Nature Cell Biol. 8

      Pages: 1291-1297

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Up-regulation of GPR48 induced by down-regulation of p27Kip1 enhances carcinoma cell invasiveness and metastasis.2006

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

      Cancer Res. 66

      Pages: 11623-11631

    • Related Report
      2006 Annual Research Report
  • [Journal Article] PKCdelta regulates collagen-induced platelet aggregation through inhibition of VASP-mediated filopodia formation.2006

    • Author(s)
      Pula, G. et al.
    • Journal Title

      Blood 108

      Pages: 4035-4044

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Double knockout mice show BASH and RKCd have different epistatic relationships in B cell maturation and CD40-mediated activation.2006

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

      lmmunol. Lett. 105

      Pages: 48-54

    • Related Report
      2006 Annual Research Report
  • [Presentation] Gdx, an X-Linked Ubiquitin-Like Modifier, Is Conjugated to Cyclin F and Regulates Mitosis2008

    • Author(s)
      N. Ishida, et. al.
    • Organizer
      4th International Conference, Ubiquitin, Ubiquitin-Like Proteins, and Cancer
    • Place of Presentation
      Huston, TX, USA
    • Year and Date
      2008-02-07
    • Related Report
      2007 Annual Research Report
  • [Presentation] 腎障害進行におけるSkp2発現亢進の解析:Skp2KOマウスを用いた検討2007

    • Author(s)
      鈴木小由理, et. al.
    • Organizer
      第30回日本分子生物学会年会・第80回日本生化学会合同大会
    • Place of Presentation
      横浜
    • Related Report
      2007 Annual Research Report
  • [Presentation] 新規ユビキチン様修飾分子GdXによるcyclin Fと細胞周期M期の制御2007

    • Author(s)
      石田典子, et. al.
    • Organizer
      第30回日本分子生物学会年会・第80回日本生化学会合同大会
    • Place of Presentation
      横浜
    • Related Report
      2007 Annual Research Report
  • [Presentation] ユビキチンリガーゼFbw7は表皮角化細胞において増殖と分化を制御する2007

    • Author(s)
      石川善則, et. al.
    • Organizer
      第30回日本分子生物学会年会・第80回日本生化学会合同大会
    • Place of Presentation
      横浜
    • Related Report
      2007 Annual Research Report
  • [Presentation] Fbxw7によるGO期維持機構とその破綻による発がん2007

    • Author(s)
      小野山一郎, et. al.
    • Organizer
      第30回日本分子生物学会年会・第80回日本生化学会合同大会
    • Place of Presentation
      横浜
    • Related Report
      2007 Annual Research Report
  • [Presentation] Gemininは着床前初期発生に必須である,第30回日本分子生物学会年会2007

    • Author(s)
      原賢太郎, et. al.
    • Organizer
      第30回日本分子生物学会年会・第80回日本生化学会合同大会
    • Place of Presentation
      横浜
    • Related Report
      2007 Annual Research Report

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Published: 2006-04-01   Modified: 2018-03-28  

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