2000 Fiscal Year Annual Research Report

血管構築の分子機構

Research Project

Project/Area Number	09281101
Research Institution	Tohoku University
Principal Investigator	佐藤靖史東北大学, 加齢医学研究所, 教授 (50178779)
Co-Investigator(Kenkyū-buntansha)	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)
Keywords	Ets-1 / アポトーシス / VEGF / シグナル伝達 / ES細胞 / 分化 / claudin-5 / テロメラーゼ
Research Abstract	(1)転写因子Ets-1は血管新生を促進するが、今回このEts-1が血管内皮細胞のアポトーシスを促進すること、さらにその機序としてBid,cytochrome p450,caspase-4,p27,p21などpro-apoptoticな遺伝子の発現を2倍以上に増強し、DAD-1,AXL,Cox-2,IAP-2,MDM-2などanti-apoptoticな遺伝子の発現を1/2以下に減弱する。(2)VEGF-Aによる細胞内シグナル伝達に関して、ERKとp38の活性化の経路が大血管の内皮細胞と細小血管の内皮細胞では異なっており血管新生に関与する細小血管内皮細胞ではRasを介したシグナル伝達が主体である。(3)トランスジェニックマウスの解析からVEGF-EはVEGF-Aと同様に血管新生を誘導するが、血管透過性促進作用は認められない。(4)VEGF2型受容体(KDR)の自己リン酸化部位の同定は1175Yとl214Yであり、特にPLCgのC末側のSH2ドメインがリン酸化1175Yと結合し、MAPKの活性化とDNA合成の誘導に必須である。(5)MadCAM-1が発生初期の静脈に特異的に発現し、MadCAM-1陽性静脈内皮の誘導にBMP-4が促進的効果を有する。(6)GFPキメラ分子をES細胞へ導入し、その細胞を内皮へ分化させて各分化段階の細胞の挙動を様々な条件でモニターすることを可能にした。(7)血管内皮細胞に特異的に発現しているclaudin-5のノックアウトマウスの作製を進め、ES細胞において破壊することに成功し、また、germlineにも通すことができた。(9)ヒト臍帯静脈内皮細胞にhTERTまたはSV40T抗原遺伝子を導入することによって、細胞の分裂寿命が延長し、無限分裂寿命の細胞株を樹立できた。この細胞株は、内皮細胞に作用する新規の増殖因子を産生することが示唆された。

Research Products
(35 results)

All Other

All Publications (35 results)

[Publications] Tanaka,M., et al.: "Expression of the 37-kDa laminin binding protein in murine lung tumor cell correlates with tumor angiogenesis."Cancer Lett.. 153. 161-168 (2000)
[Publications] 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. 19. 2138-2146 (2000)
[Publications] Sato,Y., et al.: "Properties of two VEGF receptors, Flt-1 and KDR, in the signal transduction."Ann.N.Y.Acad.Sci.. 901. 201-207 (2000)
[Publications] Nakano,T., et al.: "Angiogenesis Inhibition by Transdominant Mutant Ets-1."J.Cell.Physiol.. 184. 255-262 (2000)
[Publications] Sato,Y.: "Molecular mechanism of angiogenesis : transcription factors and their therapeutic relevance."Pharmacol.Ther.. 87. 51-60 (2000)
[Publications] Sato,Y., et al.: "Signal transduction and transcriptional regulation of angiogenesis."Adv.Exp.Med.Biol.. 476. 109-115 (2000)
[Publications] Sato,Y.: "Role of ETS family transcription factors in vascular development and angiogenesis."Cell Struct.Funct.. (in press). (2001)
[Publications] Teruyama,K., et al.: "Role of transcription factor Ets-1 in the apoptosis of human vascular endothelial cells."J.Cell.Physiol.. (in press). (2001)
[Publications] Yashima,R., et al.: "Heterogeneity of the signal transduction pathways for VEGF-indued MAPKs activation in human vascular endothelial cells."J.Cell.Physiol.. (in press). (2001)
[Publications] Maru,Y., et al.: "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)
[Publications] Chen,H., et al.: "Inhibition of vascular endothelial growth factor activity by transfection with the soluble FLT-1 gene."J.Cardiovasc.Pharmacol.. 36. 498-502 (2000)
[Publications] Maeda,Y., et al.: "Adeno-associated virus-mediated vascular endothelial growth factor gene transfer into cardiac myocytes."J.Cardiovasc.Pharmacol.. 36. 438-443 (2000)
[Publications] Sawano,A., et al.: "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)
[Publications] Takahashi,T., et al.: "The overexpression of PKCd is involved in vascular endothelial growth factor-resistant apoptosis in cultured primary sinusoidal endothelial cells."Biochem.Biophys.Res.Commun.. 280. 415-420 (2001)
[Publications] Hiratsuka,S., et al.: "Involvement of Flt-1 Tyrosine Kinase (Vascular Endothelial Growth Factor Receptor-l ) in Pathological Angiogenesis."Cancer Res.. (in press). (2001)
[Publications] Luo,J.-C., et al.: "A variant of nuclear localization signal of bipartite-type is required for the nuclear translocation of hypoxia inducible factors (la,2a and 3a)."Oncogene. (in press). (2001)
[Publications] Shibuya,M.: "Structure and dual function of vascular endothelial growth factor receptor-1 (Flt-1)."Int.J.Biochem.Cell Biol.. (in press). (2001)
[Publications] Tsukita,S.h., et al.: "Pores in the wall: Claudins constitute tight junction strands containing aqueous pores."J.Cell Biol.. 149. 13-16 (2000)
[Publications] Fujita,K., et al.: "Clostridium perfringens enterotoxin binds to the second extracellular loop of claudin-3,a tight junction integral membrane protein."FEBS Lett.. 476. 258-261 (2000)
[Publications] Sitou,M., et al.: "Complex phenotype of mice lacking occludin, a component of tight junction strands."Mol.Cell Biol.. 11. 4131-4142 (2000)
[Publications] Tsukita,Sh.: "Tight junctions involving occludin and claudins."Cornea. 19. S142-145 (2000)
[Publications] Tsukita,S.h., et al.: "The structure and function or claudins, cell adhesion molecules at tight junctions."Ann.N.Y.Acad.Sci.. 915. 129-135 (2000)
[Publications] Furuse,M., et al.: "Conversion of Zonula Occludens from tight to leaky strand type by introducing claudin-2 into MDCK I cells."J.Cell Biol.. (in press). (2001)
[Publications] Tsukita,S.h., et al.: "Multifunctional strands of tight junctions."Nature Review (Mol.Cell Biol.). (in press). (2001)
[Publications] Tanaka,Y., et al.: "Endothelin-1 is involved in the growth promotion of vascular smooth muscle cells by hyaluronic acid."Int.J.Cardiol.. 76. 39-47 (2000)
[Publications] Kaul,S.C., et al.: "Transcriptional inactivation of p53 by deletions and single amino acid changes in mouse mot-1 protein."Biochem.Biophys.Res.Commun.. 279. 602-606 (2000)
[Publications] Nishikawa,S.I., et al.: "All B cells are progeny of endothelial cells : a new perspective."Immunol Rev.. 175. 112-119 (2000)
[Publications] Kubo,H., et al.: "Vascular Endothelial Growth Factor Receptor-3 is essential for maintenance of integrity of endothelial cell lining during tumor angiogenesis. "Blood. 96. 546-553 (2000)
[Publications] Yamashita,J., et al.: "Embryonic stem cell derived Flk1-positive cells serve as vascular progenitors."Nature. 408. 92-96 (2000)
[Publications] Nagaoka,H., et al.: "Ras mediated effector patheways responsible for pre-B cell survival, which is essential for the developmental progression to the late pre-B cell stage."J.Exp.Med.. 192. 171-181 (2000)
[Publications] Yokomizo,T., et al.: "Requirement of Runx1/AML1/PEBP2B for the generation of hematopoietic and endothelial cells."Genes to Cells. 6. 13-24 (2001)
[Publications] Hemmi,H., et al.: "Temporal and spatial localization of osteoclasts in colonies from embryonic stem cells."Biochem.Biophys.Res.Commun.. 280. 526-534 (2001)
[Publications] Stacker,S.A., et al.: "Vascular endothelial growth factor-D promotes tumor growth and spread via the lymphatics. "Nature Med.. 7. 186-191 (2001)
[Publications] Makinen,T., et al.: "Inhibition of lymphangiogenesis and lymphedema in transgenic mice expressing soluble VEGF receptor 3."Nature Med. 7. 199-205 (2001)
[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)

2000 Fiscal Year Annual Research Report

血管構築の分子機構

Principal Investigator

佐藤 靖史 東北大学, 加齢医学研究所, 教授 (50178779)

Research Products

[Publications] Tanaka,M., et al.: "Expression of the 37-kDa laminin binding protein in murine lung tumor cell correlates with tumor angiogenesis."Cancer Lett.. 153. 161-168 (2000)

[Publications] 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. 19. 2138-2146 (2000)

[Publications] Sato,Y., et al.: "Properties of two VEGF receptors, Flt-1 and KDR, in the signal transduction."Ann.N.Y.Acad.Sci.. 901. 201-207 (2000)

[Publications] Nakano,T., et al.: "Angiogenesis Inhibition by Transdominant Mutant Ets-1."J.Cell.Physiol.. 184. 255-262 (2000)

[Publications] Sato,Y.: "Molecular mechanism of angiogenesis : transcription factors and their therapeutic relevance."Pharmacol.Ther.. 87. 51-60 (2000)

[Publications] Sato,Y., et al.: "Signal transduction and transcriptional regulation of angiogenesis."Adv.Exp.Med.Biol.. 476. 109-115 (2000)

[Publications] Sato,Y.: "Role of ETS family transcription factors in vascular development and angiogenesis."Cell Struct.Funct.. (in press). (2001)

[Publications] Teruyama,K., et al.: "Role of transcription factor Ets-1 in the apoptosis of human vascular endothelial cells."J.Cell.Physiol.. (in press). (2001)

[Publications] Yashima,R., et al.: "Heterogeneity of the signal transduction pathways for VEGF-indued MAPKs activation in human vascular endothelial cells."J.Cell.Physiol.. (in press). (2001)

[Publications] Maru,Y., et al.: "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)

[Publications] Chen,H., et al.: "Inhibition of vascular endothelial growth factor activity by transfection with the soluble FLT-1 gene."J.Cardiovasc.Pharmacol.. 36. 498-502 (2000)

[Publications] Maeda,Y., et al.: "Adeno-associated virus-mediated vascular endothelial growth factor gene transfer into cardiac myocytes."J.Cardiovasc.Pharmacol.. 36. 438-443 (2000)

[Publications] Sawano,A., et al.: "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)

[Publications] Takahashi,T., et al.: "The overexpression of PKCd is involved in vascular endothelial growth factor-resistant apoptosis in cultured primary sinusoidal endothelial cells."Biochem.Biophys.Res.Commun.. 280. 415-420 (2001)

[Publications] Hiratsuka,S., et al.: "Involvement of Flt-1 Tyrosine Kinase (Vascular Endothelial Growth Factor Receptor-l ) in Pathological Angiogenesis."Cancer Res.. (in press). (2001)

[Publications] Luo,J.-C., et al.: "A variant of nuclear localization signal of bipartite-type is required for the nuclear translocation of hypoxia inducible factors (la,2a and 3a)."Oncogene. (in press). (2001)

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

[Publications] Tsukita,S.h., et al.: "Pores in the wall: Claudins constitute tight junction strands containing aqueous pores."J.Cell Biol.. 149. 13-16 (2000)

[Publications] Fujita,K., et al.: "Clostridium perfringens enterotoxin binds to the second extracellular loop of claudin-3,a tight junction integral membrane protein."FEBS Lett.. 476. 258-261 (2000)

[Publications] Sitou,M., et al.: "Complex phenotype of mice lacking occludin, a component of tight junction strands."Mol.Cell Biol.. 11. 4131-4142 (2000)

[Publications] Tsukita,Sh.: "Tight junctions involving occludin and claudins."Cornea. 19. S142-145 (2000)

[Publications] Tsukita,S.h., et al.: "The structure and function or claudins, cell adhesion molecules at tight junctions."Ann.N.Y.Acad.Sci.. 915. 129-135 (2000)

[Publications] Furuse,M., et al.: "Conversion of Zonula Occludens from tight to leaky strand type by introducing claudin-2 into MDCK I cells."J.Cell Biol.. (in press). (2001)

[Publications] Tsukita,S.h., et al.: "Multifunctional strands of tight junctions."Nature Review (Mol.Cell Biol.). (in press). (2001)

[Publications] Tanaka,Y., et al.: "Endothelin-1 is involved in the growth promotion of vascular smooth muscle cells by hyaluronic acid."Int.J.Cardiol.. 76. 39-47 (2000)

[Publications] Kaul,S.C., et al.: "Transcriptional inactivation of p53 by deletions and single amino acid changes in mouse mot-1 protein."Biochem.Biophys.Res.Commun.. 279. 602-606 (2000)

[Publications] Nishikawa,S.I., et al.: "All B cells are progeny of endothelial cells : a new perspective."Immunol Rev.. 175. 112-119 (2000)

[Publications] Kubo,H., et al.: "Vascular Endothelial Growth Factor Receptor-3 is essential for maintenance of integrity of endothelial cell lining during tumor angiogenesis. "Blood. 96. 546-553 (2000)

[Publications] Yamashita,J., et al.: "Embryonic stem cell derived Flk1-positive cells serve as vascular progenitors."Nature. 408. 92-96 (2000)

[Publications] Nagaoka,H., et al.: "Ras mediated effector patheways responsible for pre-B cell survival, which is essential for the developmental progression to the late pre-B cell stage."J.Exp.Med.. 192. 171-181 (2000)

[Publications] Yokomizo,T., et al.: "Requirement of Runx1/AML1/PEBP2B for the generation of hematopoietic and endothelial cells."Genes to Cells. 6. 13-24 (2001)

[Publications] Hemmi,H., et al.: "Temporal and spatial localization of osteoclasts in colonies from embryonic stem cells."Biochem.Biophys.Res.Commun.. 280. 526-534 (2001)

[Publications] Stacker,S.A., et al.: "Vascular endothelial growth factor-D promotes tumor growth and spread via the lymphatics. "Nature Med.. 7. 186-191 (2001)

[Publications] Makinen,T., et al.: "Inhibition of lymphangiogenesis and lymphedema in transgenic mice expressing soluble VEGF receptor 3."Nature Med. 7. 199-205 (2001)

[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)

佐藤靖史東北大学, 加齢医学研究所, 教授 (50178779)