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血管内皮細胞の増殖促進と抑制の新規バランス制御分子による腫瘍血管新生制御の解析

Publicly Offered Research

Project AreaIntegrative Research on Cancer Microenvironment Network
Project/Area Number 23112513
Research Category

Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

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

Principal Investigator

東山 繁樹  愛媛大学, プロテオ医学研究センター, 教授 (60202272)

Project Period (FY) 2011-04-01 – 2013-03-31
Project Status Completed (Fiscal Year 2012)
Budget Amount *help
¥13,520,000 (Direct Cost: ¥10,400,000、Indirect Cost: ¥3,120,000)
Fiscal Year 2012: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000)
Fiscal Year 2011: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000)
Keywords腫瘍血管新生 / がん微小環境 / VEGF / Notch / BAZF / ユビキチンリガーゼ / Cullin3 / タンパク質分解
Outline of Annual Research Achievements

血管新生は、固形腫瘍増殖や組織損傷時の修復過程に必須であり、その制御は血管内皮細胞の増殖促進と抑制のバランス制御で成立している。私どもは、これまでに、血管内皮細胞の増殖促進(VEGFシグナル)と抑制(Notchシグナル)のシグナルバランスを制御する分子複合体BAZF-CUL3を同定してきた。さらに、BAZFおよびCUL3のマウス網膜でのノックダウンによる血管新生評価から、BAZFノックダウンに比べ、CUL3ノックダウンでは極めて強い血管崩壊の表現系が現れることを観察した。このことから、CUL3はBAZF以外にも異なる複合体のパートナーが存在し、血管新生に大きく絡む因子であることが強く示唆された。そこで本研究では、BAZFとCUL3の機能解析をさらに押し進め、血管新生制御の新たな分子機構の解明を目指した。まず、血管内皮細胞の細胞増殖および伸展運動に重要なシグナル伝達経路に焦点を当て詳細な解析を行った結果、CUL3ノックダウンにより、VEGFR2の蛋白質産生が顕著に抑制されることを新たに見出した。この抑制により下流シグナルのAktやErkの活性化が誘導されないことも確認した。さらには、VEGFR2の蛋白質産生の顕著な抑制は、遺伝子発現抑制ではなく、VEGFR2 mRNAの不安定化促進によるタンパク質産生の抑制によることを突き止めた。一方、細胞運動の解析から細胞の伸展力の低下が観察されたことから、細胞-基質接着に重要な接着因子とその下流シグナルの解析を行った。その結果、integrin β1蛋白質産生が極めて特異的に、且つ、顕著に抑制されていることを新たに見出した。以上の結果より、CUL3は血管内皮細胞の増殖のみならず、ネットワーク形成に必須の細胞伸展に関わる鍵分子のVEGFR2とIntegrin β1を同時に制御する極めて重要な因子であることを明らかにした。

Research Progress Status

24年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

24年度が最終年度であるため、記入しない。

Report

(2 results)
  • 2012 Annual Research Report
  • 2011 Annual Research Report
  • Research Products

    (15 results)

All 2013 2012 2011 Other

All Journal Article (10 results) (of which Peer Reviewed: 10 results) Presentation (3 results) (of which Invited: 1 results) Remarks (2 results)

  • [Journal Article] Protein kinase D2 and heat shock protein 90 beta are required for BCL6-associated zinc finger protein mRNA stabilization induced by vascular endothelial growth factor-A.2013

    • Author(s)
      Miwa D, Inoue H, Takemori N, Kurokawa M, Sakaue T, Fukuda S, Omi K, Goishi K, Higashiyama S.
    • Journal Title

      Angiogenesis

      Volume: 未定

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Cisplatin influences acquisition of resistance to molecular-targeted agents through epithelial-mesenchymal transition-like changes.2013

    • Author(s)
      Kurokawa M, Ise N, Omi K, Goishi K, Higashiyama S.
    • Journal Title

      Cancer Sci.

      Volume: 104 Issue: 7 Pages: 904-911

    • DOI

      10.1111/cas.12171

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] ErbB2 dephosphorylation and anti-proliferative effects of neuregulin-1 in ErbB2-overexpressing cell lines; re-evaluation of their low-affinity interaction.2013

    • Author(s)
      Wang, R., Iwakura, Y., Araki, K., Keino-Masu, K., Masu, M., Wang, X., Takei, N., Higashiyama, S. and Nawa, H.
    • Journal Title

      Scientific reports

      Volume: 3 Issue: 1 Pages: 1402-1402

    • DOI

      10.1038/srep01402

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Involvement of NANOG upregulation in malignant progression of human cells.2013

    • Author(s)
      Li Y., Higashiyama S., Shimakage M., Kawahara K., Yutsudo M., Watari A.
    • Journal Title

      DNA Cell Biol.

      Volume: 32(3) Issue: 3 Pages: 104-10

    • DOI

      10.1089/dna.2012.1908

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] TGFα shedding assay: An accurate and versatile method for detecting GPCR activation2012

    • Author(s)
      Asuka Inoue
    • Journal Title

      Nat Methods

      Volume: 9 Issue: 10 Pages: 1021

    • DOI

      10.1038/nmeth.2172

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Cell surface-annexins regulate ADAM-mediated ectodomain shedding of pro-amphiregulin2012

    • Author(s)
      Hironao Nakayama
    • Journal Title

      Molecular Biology of the Cell

      Volume: (印刷中) Issue: 10 Pages: 1964-1975

    • DOI

      10.1091/mbc.e11-08-0683

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A disintegrin and metalloenzyme (ADAM) 17 activation is regulated byα5β1 integrin in kidney mesangial cells2012

    • Author(s)
      Gooz P, Dang Y, Higashiyama S, Twal WO, Haycraft CJ, Gooz M.
    • Journal Title

      PLoS One

      Volume: 7 Issue: 3 Pages: e33350-e33350

    • DOI

      10.1371/journal.pone.0033350

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] BAZF, a novel component of cullin3-based E3 ligase complex, mediates VEGFR and Notch cross-signalling in angiogenesis2012

    • Author(s)
      Ohnuki H, Inoue H, Takemori N, Nakayama H, Sakaue T, Fukuda S, Miwa D, Nishiwaki E, Hatano M, Tokuhisa T, Endo Y, Nose M, and Higashiyama S
    • Journal Title

      Blood

      Volume: 119 Issue: 11 Pages: 2688-2698

    • DOI

      10.1182/blood-2011-03-345306

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Nuclear translocation of pro-amphiregulin induces chemoresistance in gastric cancer2012

    • Author(s)
      Yoshida Michihiro
    • Journal Title

      Cancer Science

      Volume: 103 Issue: 4 Pages: 708-715

    • DOI

      10.1111/j.1349-7006.2012.02204.x

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] BAZF, a novel component of cullin3-based E3 ligase complex, mediates VEGFR and Notch cross-signaling in angiogenesis2012

    • Author(s)
      Ohnuki H, Inoue H, Takemori N, Nakayama H, Sakaue T, Fukuda S, Miwa D, Nishiwaki E, Hatano M, Tokuhisa T, Endo Y, Nose M, Higashiyama S
    • Journal Title

      Blood

      Volume: 119 Pages: 2688-98

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Presentation] Regulation of ectodomain shedding in EGFR/ligand signaling2012

    • Author(s)
      Shigeki Higashiyama
    • Organizer
      International Scientific Coordination Network (ISCN) France-Japan
    • Place of Presentation
      Naruto, Japan
    • Year and Date
      2012-11-28
    • Related Report
      2012 Annual Research Report
    • Invited
  • [Presentation] BAZF mRNA-binding protein regulates stability of proangiogenic genes mRNA under a VEGF-A stimulation2012

    • Author(s)
      Hirofumi Inoue, Daisuke Miwa, Tomohisa Sakaue, Nobuaki Takemori, Katsutoshi Goishi, Shigeki Higashiyama
    • Organizer
      キーストンシンポジウム
    • Place of Presentation
      米国ユタ州Snowbird Resort
    • Related Report
      2011 Annual Research Report
  • [Presentation] ZF50 mRNA-binding protein controls vascular endotghelial growth factor-induced angiogeneic response by increasing mRNA stability of proangiogenic genes2011

    • Author(s)
      Tomohisa Sakaue, Hirofumi Inoue, Daisuke Miwa, Nobuaki Takemori, Katsutoshi Goishi, Shigeki Higashiyama
    • Organizer
      北米血管生物学会(NAVBO)
    • Place of Presentation
      米国マサチューセッツ州Cape Cod
    • Related Report
      2011 Annual Research Report
  • [Remarks] 愛媛大学プロテオサイエンスセンター 細胞増殖・腫瘍制御部門

    • URL

      http://www.m.ehime-u.ac.jp/school/biochem2/

    • Related Report
      2012 Annual Research Report
  • [Remarks]

    • URL

      http://www.m.ehime-u.ac.jp/data/course/list_detail.php?id=201100000053

    • Related Report
      2011 Annual Research Report

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Published: 2011-04-06   Modified: 2018-03-28  

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