1999 年度実績報告書

血管構築の分子機構

研究課題

研究課題/領域番号	09281101
研究機関	東北大学
研究代表者	佐藤靖史東北大学, 加齢医学研究所, 教授 (50178779)
研究分担者	三井洋司生命工学工業技術研究所, 首席研究官西川伸一京都大学, 大学院・医学研究科, 教授 (60127115) 渋谷正史東京大学, 医科学研究所, 教授 (10107427) 藤原敬己国立循環器病センター研究所, 循環器形態部長 (10190092) 月田承一郎京都大学, 大学院・医学研究科, 教授 (50155347)
キーワード	ETS-1 / HEX / Flt-1 / KDR / マウスES細胞 / Flk-1陽性細胞 / クローディン-5 / PECAM-1
研究概要	(佐藤)血管新生の過程で内皮細胞に発現するETS-1は、低酸素においてHIF-1を介して内皮細胞に誘導される。ETS-1をdominant negativeに制御する分子を作成し、adenovirus vectorに組み込むことでin vivoでの血管新生の制御を可能にした。血管新生の過程で内皮細胞に発現する転写因子HEXは、血管新生を負に制御する機能を有している。(澁谷)VEGF受容体のうち、主要な機能を果たすKDRの増殖シグナルは、KDR上の単一の自己燐酸化部位を経て、PLC_-PKCの経路で伝達される。Flt-1は、胎生期の血管形成には必要としないが、成熟個体の病的血管新生では機能する。鳥類におけるFlt-1遺伝子をクローニングした。(西川)マウスES細胞のin vitro培養系において、これまでの内皮細胞だけでなく、血管壁細胞をもFlk-1陽性細胞から分化させ、血管様構造物を構築することに成功した。(三井)エンドセリン前駆体遺伝子を導入した腫瘍細胞が造腫瘍性を失うことを示した。(月田)タイトジャンクションを構成する新しい4回膜貫通型蛋白質クローディンのうち、血管内皮に特異的に発現しているクローディン5について解析を進め、クローディン5を標的とした血管の透過性制御の可能性を示した。(藤原)PECAM-の発現を制御することで、内皮細胞の流れ刺激に反応したERKの活性化が変化することから、PECAM-1の流れ刺激受容における重要性を示した。

研究成果

(42件)

すべてその他

すべて文献書誌 (42件)

[文献書誌] Kanno, S., et al.: "Establishment of a simple and practical procedure applicable to therapeutic angiogenesis"Circulation. 99. 2682-2687 (1999)
[文献書誌] Tanaka, k., et al.: "Roles of ERK1/2 and p38 MAP kinase in the signal transduction of bFGF in endothelial cells during angiogenesis"Jpn. J. Cancer Res.. 90. 647-654 (1999)
[文献書誌] Namba, K., et al.: "Indispensable role of the transcription factor PEBP2/CBF in angiogenic activity of a murine endothelial cell MSS31"Oncogene. 19. 173-179 (2000)
[文献書誌] Sato, Y.: "Molecular mechanism of angiogenesis : transcription factors and their therapeutic relevance"Pharmacol. Therapeut.. (in press). (2000)
[文献書誌] Kanno, S., et al.: "Roles of two VEGF receptors, Flt-1 and KDR, in the signal transduction of VEGF effects in human vascular endothelial cells"Oncogene. (in press). (2000)
[文献書誌] Nakano, T., et al.: "Angiogenesis Inhibition by Transdominant Mutant Ets-1"J. Cell. Physiol.. (in press). (2000)
[文献書誌] Sato, Y., et al.: "Properties of two VEGF receptors, Flt-1 and KDR, in the signal transduction"Ann. N. Y. Acad. Sci.. (in press). (2000)
[文献書誌] Takahashi, T., et al.: "VEGF activates Protein kinase C-dependent, but Ras-independent Raf-MEK-MAP kinase pathway for DNA synthesis in primary endothelial cells"Oncogene. 18. 2221-2230 (1999)
[文献書誌] Shibuya, M., et al.: "Involvement of VEGF and its receptors in ascites tumor formation"Cancer Chemother. Pharmacol.. 43. S72-77 (1999)
[文献書誌] Shibuya, M., et al.: "Structure and function of VEGF Receptor-1 and -2"in Curr. Topics Microbiol. Immunol.. 237. 59-83 (1999)
[文献書誌] Seko, Y., et al.: "Pulsatile Stretch stimulates vascular endothelial growth factor (VEGF) secretion by cultured rat cardiac myocytes"Biochem Biophys Res Commun. 254(2). 462-465 (1999)
[文献書誌] Mashiba, S., et al.: "Inhibition of hepatic stellate cell contraction during activation in vitro by vascular endothelial growth factor in association with upregulation of FLT tyrosine kinase receptor family, FLT-1"Biochem Biophys Res Commun. 258. 674-678 (1999)
[文献書誌] Maruyama, K., et al.: "Interleukin-1 beta upregulates cardiac expression of vascular endothelial growth factor and its receptor KDR/flk-1 via activation of protein tyrosine kinases"J Mol Cell Cardiol. 31. 607-617 (1999)
[文献書誌] Katoh, H., et al.: "Expression of vascular endothelial growth factor (VEGF) in human thyroid neoplasms"Hum. Pathol. 30. 891-897 (1999)
[文献書誌] Yoshiji, H., et al.: "Protein kinase C lies on the signaling pathway for vascular endothelial growth factor-mediated tumor development and angiogenesis"Cancer Res.. 59. 4413-4418 (1999)
[文献書誌] Wakiya, K., et al.: "Okadaic acidstimulates the expression of vascular endothelial growth factor gene"Biochem Biophys Res Commun. 265. 584-588 (1999)
[文献書誌] Fellmer, PT., et al.: "Vascular endothelial growth factor-C gene expression in papillary and follicular thyroid carcinomas"Surgery. 126. 1056-1062 (1999)
[文献書誌] Hirashima, M., et al.: "Maturation of embryonic stem cells into endothelial cells in an in vitro model of vasculogenesis"Blood. 93. 1253-1263 (1999)
[文献書誌] Ogawa, M., et al.: "Expression of a4-integrin defines the earliest percursor of hematopoietic cell lineage diverged from endothelial cells"Blood. 93. 1168-1177 (1999)
[文献書誌] Murayama, T., et al.: "Intraperitoneal administration of anti-c-fms monoclonal antibody prevents the initital events of atherogenesis but dose not reduce the size of advanced lesion in apolipoprotein E-deficient mice"Circulation. 99. 1740-1746 (1999)
[文献書誌] Niida, S., et al.: "Vascular endothelial growth factor can substitute for macrophage colony-stimulating factor in the support of osteoclastic bone resorption"J. Exp. Med.. 190. 293-298 (1999)
[文献書誌] Ikeda, W., et al.: "Afadin : a key molecule essential for structural organization of ceell-cell junctions of polarized epithelia during embryogenesis"J. Cell Biol.. 146. 1117-1131 (1999)
[文献書誌] Nishikawa, SI., et al.: "All B cells are progeny of endothelial cells : A new perspective"Immunol Rev. (in press). (2000)
[文献書誌] Nishikawa, SI., et al.: "Inflammation, a prototype for organogenesis of lympho-hematopoietic system"Curr Opin Immunol. (in press). (2000)
[文献書誌] Shinoda, E., et al.: "Tissue factor pathway inhibitor-2 is a novel mitogen for vascular smooth muscle cells"J. Biol. Chem.. 274(9). 5379-5384 (1999)
[文献書誌] Uchida, T., et al.: "Geneexpression of vasoactive intestinal contractor / endothelin-2 in ovary, uterus and embryo"J. Mol. Endocrinol.. 22(2). 161-171 (1999)
[文献書誌] Takano, S., et al.: "Expression of the angiogenic factor thymidine phosphorylase in human astrocytic tumors"J. Cancer Res. Clin. Oncol.. (in press). (2000)
[文献書誌] Morita, K., et al.: "Claudin multigene family encoding four-transmembrane domain protein components of tight junction strands"Proc. Natl. Acad. Sci. USA. 96. 511-516 (1999)
[文献書誌] Morita, K., et al.: "Claudin-11/OSP-based tight junctions in myelinated sheaths of oligodendrocytes and in Sertoli cells in testis"J. Cell Biol. 145. 597-588 (1999)
[文献書誌] Tsukita, Sh., et al.: "Occludin and claudins in tight junction strands : Leading or supporting palyers?"Trends in Cell Biol. 9. 268-273 (1999)
[文献書誌] Tsukita, Sh., et al.: "Structural and signaling molecules come together at tight junctions"Curr. Opin. Cell Biol.. 11. 628-633 (1999)
[文献書誌] Kubota, K., et al.: "Ca++-independent cell adhesion activity of claudins, integral membrane proteins of tight junctions"Curr Biol.. 9. 1035-1038 (1999)
[文献書誌] Sonoda, N., et al.: "Clostridium perfringens enterotoxin fragment removes specific claudins from tight junction strands : Evidence for direct involvement of claudins in tight junction barrier"J. Cell Biol.. 147. 195-204 (1999)
[文献書誌] Morita, K., et al.: "Endothelial claudin : claudin-5/TMVCF constitutes tight junction strands in endothelial cells"J. Cell Biol.. 147. 185-194 (1999)
[文献書誌] Furuse, M., et al.: "Manner of interaction of heterogenous claudin species within and between tight junction strands"J. Cell Biol.. 147. 891-907 (1999)
[文献書誌] Itoh, M., et al.: "Molecular basis for the recruitment of three MAGUKs, ZO-1, ZO-2 and ZO-3, totight Junctions : Direct binding of their first PDZ domains to the COOH-termini of claudins"J. Cell Biol.. 147. 1351-1367 (1999)
[文献書誌] Hosokawa, H., et al.: "Neuron-specific expression of cationic amino acid transporter 3 in the adult rat brain"Brain Res.. 838. 158-165 (1999)
[文献書誌] Kojima, S., et al.: "SH1 (cysteine 717) of smooth muscle myosin Its role in the motor function"Biochemistry. 38. 11670-11676 (1999)
[文献書誌] Kano,Y., et al.: "The lateral zone of cell-cell adhesion as the maior fluid shear stress related signal transduction site"Circ. Res.. (in press). (2000)
[文献書誌] Katoh, K., et al.: "Isolation and in vitro contraction of stress fibers. In Regulation and Effectors of Small GTPases"Methods in Enzymology. (in press). (2000)
[文献書誌] Sato, Y., et al.: "Angiogenesis ; From molecular to Integrative Pharmacology"Kluwer Academic/Plenum Publisher(in press). (2000)
[文献書誌] Nishikawa, SI., et al.: "Hematopoiesis, developmental approach"Oxford University Press(in press). (2000)

1999 年度 実績報告書

血管構築の分子機構

研究代表者

佐藤 靖史 東北大学, 加齢医学研究所, 教授 (50178779)

研究成果

[文献書誌] Kanno, S., et al.: "Establishment of a simple and practical procedure applicable to therapeutic angiogenesis"Circulation. 99. 2682-2687 (1999)

[文献書誌] Tanaka, k., et al.: "Roles of ERK1/2 and p38 MAP kinase in the signal transduction of bFGF in endothelial cells during angiogenesis"Jpn. J. Cancer Res.. 90. 647-654 (1999)

[文献書誌] Namba, K., et al.: "Indispensable role of the transcription factor PEBP2/CBF in angiogenic activity of a murine endothelial cell MSS31"Oncogene. 19. 173-179 (2000)

[文献書誌] Sato, Y.: "Molecular mechanism of angiogenesis : transcription factors and their therapeutic relevance"Pharmacol. Therapeut.. (in press). (2000)

[文献書誌] Kanno, S., et al.: "Roles of two VEGF receptors, Flt-1 and KDR, in the signal transduction of VEGF effects in human vascular endothelial cells"Oncogene. (in press). (2000)

[文献書誌] Nakano, T., et al.: "Angiogenesis Inhibition by Transdominant Mutant Ets-1"J. Cell. Physiol.. (in press). (2000)

[文献書誌] Sato, Y., et al.: "Properties of two VEGF receptors, Flt-1 and KDR, in the signal transduction"Ann. N. Y. Acad. Sci.. (in press). (2000)

[文献書誌] Takahashi, T., et al.: "VEGF activates Protein kinase C-dependent, but Ras-independent Raf-MEK-MAP kinase pathway for DNA synthesis in primary endothelial cells"Oncogene. 18. 2221-2230 (1999)

[文献書誌] Shibuya, M., et al.: "Involvement of VEGF and its receptors in ascites tumor formation"Cancer Chemother. Pharmacol.. 43. S72-77 (1999)

[文献書誌] Shibuya, M., et al.: "Structure and function of VEGF Receptor-1 and -2"in Curr. Topics Microbiol. Immunol.. 237. 59-83 (1999)

[文献書誌] Seko, Y., et al.: "Pulsatile Stretch stimulates vascular endothelial growth factor (VEGF) secretion by cultured rat cardiac myocytes"Biochem Biophys Res Commun. 254(2). 462-465 (1999)

[文献書誌] Mashiba, S., et al.: "Inhibition of hepatic stellate cell contraction during activation in vitro by vascular endothelial growth factor in association with upregulation of FLT tyrosine kinase receptor family, FLT-1"Biochem Biophys Res Commun. 258. 674-678 (1999)

[文献書誌] Maruyama, K., et al.: "Interleukin-1 beta upregulates cardiac expression of vascular endothelial growth factor and its receptor KDR/flk-1 via activation of protein tyrosine kinases"J Mol Cell Cardiol. 31. 607-617 (1999)

[文献書誌] Katoh, H., et al.: "Expression of vascular endothelial growth factor (VEGF) in human thyroid neoplasms"Hum. Pathol. 30. 891-897 (1999)

[文献書誌] Yoshiji, H., et al.: "Protein kinase C lies on the signaling pathway for vascular endothelial growth factor-mediated tumor development and angiogenesis"Cancer Res.. 59. 4413-4418 (1999)

[文献書誌] Wakiya, K., et al.: "Okadaic acidstimulates the expression of vascular endothelial growth factor gene"Biochem Biophys Res Commun. 265. 584-588 (1999)

[文献書誌] Fellmer, PT., et al.: "Vascular endothelial growth factor-C gene expression in papillary and follicular thyroid carcinomas"Surgery. 126. 1056-1062 (1999)

[文献書誌] Hirashima, M., et al.: "Maturation of embryonic stem cells into endothelial cells in an in vitro model of vasculogenesis"Blood. 93. 1253-1263 (1999)

[文献書誌] Ogawa, M., et al.: "Expression of a4-integrin defines the earliest percursor of hematopoietic cell lineage diverged from endothelial cells"Blood. 93. 1168-1177 (1999)

[文献書誌] Murayama, T., et al.: "Intraperitoneal administration of anti-c-fms monoclonal antibody prevents the initital events of atherogenesis but dose not reduce the size of advanced lesion in apolipoprotein E-deficient mice"Circulation. 99. 1740-1746 (1999)

[文献書誌] Niida, S., et al.: "Vascular endothelial growth factor can substitute for macrophage colony-stimulating factor in the support of osteoclastic bone resorption"J. Exp. Med.. 190. 293-298 (1999)

[文献書誌] Ikeda, W., et al.: "Afadin : a key molecule essential for structural organization of ceell-cell junctions of polarized epithelia during embryogenesis"J. Cell Biol.. 146. 1117-1131 (1999)

[文献書誌] Nishikawa, SI., et al.: "All B cells are progeny of endothelial cells : A new perspective"Immunol Rev. (in press). (2000)

[文献書誌] Nishikawa, SI., et al.: "Inflammation, a prototype for organogenesis of lympho-hematopoietic system"Curr Opin Immunol. (in press). (2000)

[文献書誌] Shinoda, E., et al.: "Tissue factor pathway inhibitor-2 is a novel mitogen for vascular smooth muscle cells"J. Biol. Chem.. 274(9). 5379-5384 (1999)

[文献書誌] Uchida, T., et al.: "Geneexpression of vasoactive intestinal contractor / endothelin-2 in ovary, uterus and embryo"J. Mol. Endocrinol.. 22(2). 161-171 (1999)

[文献書誌] Takano, S., et al.: "Expression of the angiogenic factor thymidine phosphorylase in human astrocytic tumors"J. Cancer Res. Clin. Oncol.. (in press). (2000)

[文献書誌] Morita, K., et al.: "Claudin multigene family encoding four-transmembrane domain protein components of tight junction strands"Proc. Natl. Acad. Sci. USA. 96. 511-516 (1999)

[文献書誌] Morita, K., et al.: "Claudin-11/OSP-based tight junctions in myelinated sheaths of oligodendrocytes and in Sertoli cells in testis"J. Cell Biol. 145. 597-588 (1999)

[文献書誌] Tsukita, Sh., et al.: "Occludin and claudins in tight junction strands : Leading or supporting palyers?"Trends in Cell Biol. 9. 268-273 (1999)

[文献書誌] Tsukita, Sh., et al.: "Structural and signaling molecules come together at tight junctions"Curr. Opin. Cell Biol.. 11. 628-633 (1999)

[文献書誌] Kubota, K., et al.: "Ca++-independent cell adhesion activity of claudins, integral membrane proteins of tight junctions"Curr Biol.. 9. 1035-1038 (1999)

[文献書誌] Sonoda, N., et al.: "Clostridium perfringens enterotoxin fragment removes specific claudins from tight junction strands : Evidence for direct involvement of claudins in tight junction barrier"J. Cell Biol.. 147. 195-204 (1999)

[文献書誌] Morita, K., et al.: "Endothelial claudin : claudin-5/TMVCF constitutes tight junction strands in endothelial cells"J. Cell Biol.. 147. 185-194 (1999)

[文献書誌] Furuse, M., et al.: "Manner of interaction of heterogenous claudin species within and between tight junction strands"J. Cell Biol.. 147. 891-907 (1999)

[文献書誌] Itoh, M., et al.: "Molecular basis for the recruitment of three MAGUKs, ZO-1, ZO-2 and ZO-3, totight Junctions : Direct binding of their first PDZ domains to the COOH-termini of claudins"J. Cell Biol.. 147. 1351-1367 (1999)

[文献書誌] Hosokawa, H., et al.: "Neuron-specific expression of cationic amino acid transporter 3 in the adult rat brain"Brain Res.. 838. 158-165 (1999)

[文献書誌] Kojima, S., et al.: "SH1 (cysteine 717) of smooth muscle myosin Its role in the motor function"Biochemistry. 38. 11670-11676 (1999)

[文献書誌] Kano,Y., et al.: "The lateral zone of cell-cell adhesion as the maior fluid shear stress related signal transduction site"Circ. Res.. (in press). (2000)

[文献書誌] Katoh, K., et al.: "Isolation and in vitro contraction of stress fibers. In Regulation and Effectors of Small GTPases"Methods in Enzymology. (in press). (2000)

[文献書誌] Sato, Y., et al.: "Angiogenesis ; From molecular to Integrative Pharmacology"Kluwer Academic/Plenum Publisher(in press). (2000)

[文献書誌] Nishikawa, SI., et al.: "Hematopoiesis, developmental approach"Oxford University Press(in press). (2000)

1999 年度実績報告書

佐藤靖史東北大学, 加齢医学研究所, 教授 (50178779)