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腫瘍の形成と維持の機構

Research Project

Project/Area Number 12215024
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionThe University of Tokyo

Principal Investigator

渋谷 正史  東京大学, 医科学研究所, 教授 (10107427)

Co-Investigator(Kenkyū-buntansha) 後藤 典子  東京大学, 医科学研究所, 講師 (10251448)
矢花 直幸  東京大学, 医科学研究所, 助手 (90292846)
櫻井 佳子  東京大学, 医科学研究所, 助手 (10361619)
大場 基  昭和大学, 腫瘍分子医学研究所, 助手 (70297018)
中村 佐千枝  東京大学, 医科学研究所, 助手 (60313087)
丸 義朗  東京大学, 医科学研究所, 助教授 (00251447)
Project Period (FY) 2000 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥213,000,000 (Direct Cost: ¥213,000,000)
Fiscal Year 2004: ¥60,000,000 (Direct Cost: ¥60,000,000)
Fiscal Year 2003: ¥38,000,000 (Direct Cost: ¥38,000,000)
Fiscal Year 2002: ¥38,000,000 (Direct Cost: ¥38,000,000)
Fiscal Year 2001: ¥32,000,000 (Direct Cost: ¥32,000,000)
Fiscal Year 2000: ¥45,000,000 (Direct Cost: ¥45,000,000)
Keywords腫瘍血管 / VEGF / VEGF受容体 / ノックインマウス / シグナル伝達 / 血管新生 / VEGFR-2 / VEGFR-1 / がん転移 / 血管透過性 / VEGFR-2 (KDR) / VEGFR-1 (Flt-1) / VEGFR-2(KDR) / VEGFR-1(Flt-1) / 系統発生 / トランスジェニックマウス / VEGF-E
Research Abstract

VEGFとその受容体のシグナル伝達機構をマウス個体レベルで解析し、(1)内皮細胞増殖の主なポジティブシグナルを発信するのはVEGF受容体2(KDR/Flk-1)であること、また自己リン酸化部位1173チロシンは血管発生・新生に必須であること、を明らかにした。すなわち、1173チロシンをフェニールアラニンに置換したマウス(1173F/Fマウス)を作出して解析したところ、この変異マウスは血管系をほとんど構築することができず、胎生8.5-9.0日で死亡することが明らかとなった。この部位はPLCgamma-PKC-MAPキナーゼ経路の開始点であり、腫瘍血管系制御の新規分子標的として利用できると期待される。(2)発生早期におけるVEGF受容体の役割をキナーゼ阻害剤などにより解析し、受容体発現細胞(ヘマンジオブラスト)をVEGF-A濃度勾配に依存して頭部へ遊走させるのが重要な機能であることを明らかにした。(3)FRS2ファミリードッキング分子FRS2αの変異マウスの解析より、FRS2αが、FGF受容体によって活性化することにより、胎盤及び網膜の幹細胞の維持、増殖に重要な役割を果たすことが明らかとなった。(4)FRS2βは、EGF受容体シグナル伝達を抑制的に制御することが示された。(5)上皮特異的な増殖抑制・分化誘導作用を有するPKCηは、cyclin D1の発現抑制とトランスグルタミナーゼ1の酵素活性上昇を伴って、E-cadherin、β/γ-cateninを発現するヒト食道扁平上皮癌細胞の増殖を抑制した。この増殖抑制能は、ヌードマウスを用いた皮膚担癌実験により、個体レベルでも確認された。

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

    (34 results)

All 2005 2004 Other

All Journal Article (6 results) Publications (28 results)

  • [Journal Article] Membrane-fixation of VEGFR1 ligand-binding domain is important for vasculogenesis/angiogenesis in mice.2005

    • Author(s)
      Hiratsuka, S., Nakao, K., Nakamura, K., Katsuki, M., Maru, Y., Shibuya, M.
    • Journal Title

      Mol.Cell.Biol. 25

      Pages: 346-354

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Essential role of Flk-1 (vascular endothelial growth factor receptor-2) tyrosine residue-1173 in vasculogenesis in mice.2005

    • Author(s)
      Sakurai, Y., Ohgimoto, K., Kataoka, Y., Yoshida, N., Shibuya, M.
    • Journal Title

      Proc.Natl.Acad.Sci.USA 102

      Pages: 1076-1081

    • Related Report
      2004 Annual Research Report
  • [Journal Article] A Novel Snake Venom Vascular Endothelial Growth Factor (VEGF) Predominantly Induces Vascular Permeability through Preferential Signaling via VEGF Receptor-1.2004

    • Author(s)
      Takahashi, H., Hattori, S., Iwamatsu, A., Takizawa, H., Shibuya, M.
    • Journal Title

      J.Biol.Chem. 279

      Pages: 46304-46314

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Tyrosine phosphorylation sites on FRS2alpha responsible for Shp2 recruitment are critical for induction of lens and retina.2004

    • Author(s)
      Gotoh, N., Ito, M., Yamamoto, S., Yoshino, I, Song, N., Wang, Y., Lax, I., Schlessinger, J., Shibuya, M., Lang, R.A.
    • Journal Title

      Proc.Natl.Acad.Sci.USA 101

      Pages: 17144-17149

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Development of primitive and definitive hematopoiesis from nonhuman primate embryonic stem cells in vitro.2004

    • Author(s)
      Umeda, K., Heike, T., Yoshimoto, M., Shiota, M., Suemori, H., Luo, H.Y., Chui, D.H., Torii, R., Shibuya, M., Nakatsuji, N., Nakahata, T.
    • Journal Title

      Development 131

      Pages: 1869-1879

    • Related Report
      2004 Annual Research Report
  • [Journal Article] The c-Cb1/CD2AP complex regulates VEGF-induced endocytosis and degradation of Flt-1 (VEGFR-1).2004

    • Author(s)
      Kobayashi, S., Sawano, A., Nojima, Y., Shibuya, M., Maru, Y.
    • Journal Title

      FASEB J. 18

      Pages: 929-931

    • Related Report
      2004 Annual Research Report
  • [Publications] Kiba, A., Yabana, N., Shibuya, M.: "A set of loop-1 and -3 structures in the novel VEGF family member, VEGF-ENZ-7, is essential for the activation of VEGFR-2 signaling"J.Biol.Chem.. 278. 13453-13461 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kiyono, M., Shibuya, M.: "Bone morphogenetic protein 4 mediates apoptosis of capillary endothelial cells during rat pupillary membrane regression"Mol.Cell Biol.. 23. 4627-4636 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Autiero, M., Waltenberger, J., Communi, D., Kranz, A., Moons, L., Lambrechts, D., Kroll, J., Plainsance, S., De Mol, M., Bono, F., Kliche, S., Fellbrich, G., Ballmer-Hofer, K., Maglione, D., Mayr-Beyrle, U., Dewerchin, M., Dombrowski, S., Stanimovic, D., Humnelen, P.V., Dehio, C., Hicklin, D., Persico, G., Herbert, J.M., Communi, D., Shibuya, M., Collen, D., Conway, E.M., Carmeliet, P.: "Role of P1GF in the intra-and inter-molecular crolltalk between VEGF receptors Flt1 and Flk1"Nature Med.. 9. 936-943 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Sasaki, A., Taketomi, T., Kato, R., Saeki, K., Nonami, A., Sasaki, M., Kuriyama, M., Saito, N., Shibuya, M., Yoshimura: "Mammalian Sprouty4 suppresses Ras-independent ERK activation by binding to Raf1"Nature Cell Biol.. 5. 427-432 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Gotoh, N., Laks, S., Nakashima, M., Lax, I., Schlessinger, J.: "FRS2 family docking proteins with overlapping roles in activation of MAP kinase have distinct spatial-temporal patterns of expression of their transcripts"FEBS lett.. (in press).

    • Related Report
      2003 Annual Research Report
  • [Publications] Matsumura, M, Tanaka, N., Kuroki, T., Ichihashi M, Ohba, M.: "The η isoform of protein kinase C inhibits UV-induced activation of caspase-3 in normal human keratinocytes"Biochem.Biophys.Res.Commun.. 303. 350-356 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Shibuya, M.: "Vascular endothelial growth factor receptor family genes : When did the three genes phylogenetically segregate?"Biol. Chem.. 383. 1573-1579 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yabana, N., Shibuya, M.: "Adaptor Protein APS Binds the NH_2-Terminal Autoinhihitory Domain of Guanine Nucleotide Exchange Factor Vav3 and Augments its Activity"Oncogene. 21. 7720-7729 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hiratsuka, S., Nakamura, K., Iwai, S., Murakami, M., Itoh, T., Kijima, H., Shipley, J.M., Senior, R.M., Shibuya, M.: "MIMP9 induction by Vascular Endothelial Growth Factor Receptor-1 is involved in lung specific metastasis"Cancer Cell. 2. 289-300 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kiba, A., Yabana, N., Shibuya, M.: "A set of loop-1 and -3 structures in the novel VIEGF family member, VEGF-ENZ-7, is essential for the activation of VEGFR-2 signaling"J. Biol. Chem.. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nakamura, T., Komiya, M., Sone, K., Hirose, E., Gotoh, N., Morii, H.Ohta, Y., Mori, N.: "Grit, a GTPase-activating protein for the Rho family, regulates neurite extension through association with the TrkA receptor and N-Shc and Crk/Crk adapter molecules"Mol. Cell. Biol.. 22. 8721-8734 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Matsumura M, Tanaka N., Kuroki T., Ichihashi M, Ohba M.: "The η isoform of protein kinase C inhibits UV-induced activation of caspase-3 in normal human keratinocytes"Biochem. Biophys. Res. Commun.. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Sawano, A., Iwai, S., Sakurai, Y., Ito, M., Shitara, K., Nakahata, T., Shibuya, M.: "Vascular Endothelial Growth Factor Receptor-1(Flt-1) is a Novel Cell Surface Marker for the Lineage of Monocyte-Macrophages in humans"Blood. 97. 785-791 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hiratsuka, S., Maru, Y., Okada, A., Seiki, M., Noda, T., Shibuya, M.: "Involvement of Fit-1 Tyrosine Kinase (Vascular Endothelial Growth Factor Receptor-1) in Pathological Angiogenesis"Cancer Res.. 61. 1207-1213 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Luo, J.-C., Shibuya, M.: "A variant of nuclear localization signal of bipartite-type is required for the nuclear translocation of hypoxia inducible factors (1α,2α and 3α)"Oncogene. 20. 1435-1444 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kin, Y., Shibuya, M., Maru, Y.: "Inhibition of protein kinase C delta has negative effect on anchorage-independent growth of BCR-ABL-transformed Rat1 cells"Leuk. Res.. 25. 821-825 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Takahashi, T., Yamaguchi, S., Chiba, K., Shibuya, M.: "A single autophosphorylation site on KDR/Flk-1 is essential for VEGF-A-dependent activation of PLC-γ and DNA synthesis in vascular endothelial cells"EMBO J.. 20. 2768-2778 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Maru, Y., Bergmann, E., Coin, F., Egly, J., Shibuya, M.: "TFIIH functions are altered by the P21OBCR-ABL oncoprotein produced on the Philadelphia chromosome"Mutat. Res.. 483. 83-88 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Maru,Y.,Hirosawa,H.,and Shibuya,M: "An oncogenic form of the Flt-1 kinase has a tubulogenic potential in a sinusoidal endothelial cell line."Eur.J.Cell.Biol.. 79. 130-143 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Shibuya,M.: "Structure and dual function of vascular endothelial growth factor receptor-1 (Flt-1)."Int.J.Biochem.Cell Biol.,. (in press.). 2001

    • Related Report
      2000 Annual Research Report
  • [Publications] Kanno S,Oda N,Abe M,Terai Y,Ito M,Shitara K,Tabayashi K,Shibuya M,Sato Y.: "Roles of two VEGF receptors, Flt-1 and KDR, in the signal transduction of VEGF effects in human vascular endothelial cells."Oncogene. 19. 2138-2146 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Shibuya,M.: "Development of the liver vascular system, in Morphogenesis of Endothelium, edited by W.Risau, and G.M.Rubanyi,"Harwood Academic Publishers,. 175-188 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Sawano,A.,Iwai,S.,Sakurai,Y.,Ito,M.,Shitara,K,Nakahata,T.,and Shibuya,M.: "Vascular Endothelial Growth Factor Receptor-1 (Flt-1) is a Novel Cell Surface Marker for the Lineage of Monocyte-Macrophages in Humans."Blood.. 97. 785-791 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Chen H,Ikeda U,Shimpo M,Maeda Y,Shibuya M,Ozawa K,Shimada K: "Inhibition of vascular endothelial growth factor activity by tranfection with the soluble FLT-1 gene."J Cardiovasc Pharmacol. 36. 498-502 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Maeda Y,Ikeda U,Shimpo M,Shibuya M,Monahan J,Urabe M,Ozawa K,Shimada K.: "Adeno-associated virus-mediated vascular endothelial growth factor gene transfer into cardiac myocytes."J Cardiovasc Pharmacol.. 4. 438-443 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Takahashi,T.and Shibuya,M.: "The overexpression of PKCδ is involved in vascular endothelial growth factor-resistant apoptosis in cultured primary sinusoidal endothelial cells."Biochem Biophys Res Commun.. 280. 415-420 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Hiratsuka,S.,Maru,Y.,Okada,A.,Seiki,M.,Noda,T.,and Shibuya,M.: "Involvement of Flt-1 Tyrosine Kinase (Vascular Endothelial Growth Factor Receptor-1) in Pathological Angiogenesis"Cancer Res.,. (in press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Luo,J.-C.,and Shibuya,M.: "A variant of nuclear localization signal of bipartite-type is required for the nuclear translocation of hypoxia inducible factors (1α, 2α and 3α)."Oncogene,. (in press). (2001)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2018-03-28  

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