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酸化ストレスを伴う哺乳類細胞の生物学的系における抗酸化分子とチロシンキナーゼ

Research Project

Project/Area Number 12147202
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionTokyo Women's Medical University (2002-2004)
The University of Tokyo (2000-2001)

Principal Investigator

丸 義朗  東京女子医科大学, 医学部, 教授 (00251447)

Project Period (FY) 2000 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥31,500,000 (Direct Cost: ¥31,500,000)
Fiscal Year 2004: ¥7,900,000 (Direct Cost: ¥7,900,000)
Fiscal Year 2003: ¥7,800,000 (Direct Cost: ¥7,800,000)
Fiscal Year 2002: ¥7,700,000 (Direct Cost: ¥7,700,000)
Fiscal Year 2001: ¥8,100,000 (Direct Cost: ¥8,100,000)
Keywords活性酸素 / チロシンキナーゼ / Nox / 血管内皮細胞 / 卵細胞 / 金属 / 血管 / 活性酵素 / PAI-1 / HSC70 / エンドサイトーシス / 金属蛋白 / Nox1 / CD2AP / VEGF / Flt-1 / ABL / 癌細胞 / THIIH / PKC / メタロプロテアーゼ / HBP23 / 2原子分子
Research Abstract

(1)直接的に活性酸素の産生に関与する分子である古典的なNADPHオキシダーゼ複合体は現在Nox2と命名されており、これと相同性を有する分子が複数同定されている。その一つであるNox1が肝臓の類洞の内皮細胞で発現していることを見い出した。同細胞の初代培養では血管内皮細胞増殖因子(VEGF)依存性の細胞増殖を認めるが、Nox1はこれと平行して転写を介した発現上昇を示した。これに対して、Nox2の発現はmRNAのレベルで変化を認めなかった。ところがNox1自体の生物学的活性は逆説的にも細胞死であり、そのsiRNAや活性酸素のスカベンジャーなどの投与でVEGF抵抗性の細胞死は回復した。すなわち転写が誘導されたNox1の活性はVEGFの活性と拮抗するものであった。さらに、Nox1を肝類洞の内皮細胞株で過剰発現させるとマトリゲル上で毛細血管様のネットワークを形成した。この現象も抗酸化作用を有する化学物質で抑制された。興味あることにVEGF受容体の恒常的活性化型を発現させると管腔形成が認められるのみ対し、Nox1のそれは管腔を形成していなかった。
(2)受精時に活性酸素が関与することは古くから知られている。我々はマウス卵細胞ではNox2が中心的に発現していることを見い出した。さらにウニ卵でNox相同性遺伝子を探索し、新規Nox遺伝子Nox-U1を発見した。遺伝子進化論的にはNox2からはむしろ分岐し、Nox4やNox5に近縁な遺伝子であることも報告した。FADやNADPHの結合に関与する領域、膜貫通部分などは極めてよく保存されていた。現在抗体を作成し、受精への関与を研究中である。

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

(17 results)

All 2004 Other

All Journal Article (2 results) Publications (15 results)

  • [Journal Article] Nox1 regulates formation of capillary-like networks and vascular endothelial growth factor-resistant apoptosis in sinusoidal endothelial cells2004

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

      Exp.Cell Res. 300

      Pages: 455-462

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Expression of Nox genes in rat organs, mouse oocytes, and sea urchin eggs

    • Author(s)
      Maru et al.
    • Journal Title

      DNA Sequences (印刷中)

    • Related Report
      2004 Annual Research Report
  • [Publications] Uchida, Y.et al.: "Cellular carbonyl stress enhances the expression of plasminogen activator inhibitor-1 in rat white adipocytes via reactive oxygen species-dependent pathway."J.Biol.Chem.. (in press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Tsukahara, F., Maru, Y.: "Identification of novel nuclear export and nuclear localization-related signals in human heat shock cognate protein 70."J.Biol.Chem.. (in press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kobayashi, S et al.: "The c-Cbl/CD2AP complex regulates VEGF-induced endocytosis and degradation of Flt-1 (VEGFR-1)"FASEB J.. (in press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kobayashi, S.et al.: "Dynamic regulation of gene expression by the Flt-1 kinase and Matrigel in endothelial tubulogenesis."Geneomics. (in press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kin, Y., Shibuya, M., Maru, Y.: "Inhibition of protein kinase C δ has negative effect on anchorage-independent growth of BCR-ABL-transformed Rat1 cells"Leukemia Res.. 25. 821-825 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Maru, Y., K.Hanks, S.K., Shibuya, M.: "The tubulogenic activity associated with an activated form of Flt-1 kinase is dependent on focal adhesion kinase"Mol. Cell Res., Biochim. et Biophy. Acta. 1540. 147-153 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Itoh, Y., Takamura, A., Itoh, N., Maru, Y., Sato, H., Suenaga, N., Aoki, T., Seiki, M.: "Homophilic complex formation of MT1-MMP facilitates proMMP-2 activation on the cell surface and promotes tum or cell invasion"EMBO J.. 20. 4782-4793 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kin, Y., Shibuya, M., Maru, Y.: "A suppressive effect of an Epstein-Bar virus-immortalized cell line on leukemic cells"Clinical Biochemistry. 34. 507-510 (2001)

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

    • Related Report
      2001 Annual Research Report
  • [Publications] Kin, Y., Li, G., Shibuya, M., Maru, Y.: "The Dbl-homology domain of BCR is not a simple spacer in P210BCR-ABL of the Philadelphia chromosome"J. Biol. Chem.. 276. 39462-39468 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Maru,Y.: "Use of glutathione S-transferase (GST) as an artificial dimerization domain to activate oncogenes that require multimerization."Methods in Enzymology. 327. 429-440 (2000)

    • Related Report
      2000 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] Maru,Y.: "Molecular biology of chronic myeloid leukemia."Int.J.Hematology. in press (印刷中). (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 (印刷中). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kin,Y.,Shibuya,M.,and Maru,M.: "Inhibition of protein kinase C_-has negative effect on anchorage-independent growth of BCR-ABL-transformed Rat1 cells."Leukemia Res.. in press (印刷中). (2001)

    • Related Report
      2000 Annual Research Report

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Published: 2001-03-31   Modified: 2018-03-28  

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