生理的ブレーキシステム解明による抗血管、リンパ管新生阻害へのアプローチ

• Project/Area Number: 20013012
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: The University of Tokyo
• Principal Investigator: 南 敬 東京大学, 先端科学技術研究センター, 特任准教授 (00345141)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥11,900,000 (Direct Cost: ¥11,900,000); Fiscal Year 2009: ¥5,800,000 (Direct Cost: ¥5,800,000); Fiscal Year 2008: ¥6,100,000 (Direct Cost: ¥6,100,000)
• Keywords: 血管内皮細胞 / ダウン症候群 / NFAT / Egr-3 / 腫瘍血管 / 血管新生 / 敗血症 / Heterogeneity / NFATc / DSCN-1s / Hprt-locus / Egr3 / GATA / heterogeneity / Angiogenesis / Inflammation

Research Abstract

血管内皮活性化に寄与するVEGF/thrombin刺激での遺伝子変動網羅的解析から早期に最大に誘導されるダウン症候群関連因子(DSCR)-1s及び2番自に強く誘導される転写因子Egr-3を見出した。DSCR-1sはCalcineurin-NFAT経路によって発現誘導され、NFATの更なる活性化をブロックするfeedback機構を有するが、このpromoter領域をHprt-locusにknock-inしたマウス解析から、in vivoにおいてもDSCR-1sはVEGF応答のprimary targetであること、及び血管新生性・炎症性刺激の負荷に伴い、腫瘍血管を含む血管系に限局してDSCR-1sが強く誘導されることが判明した。またDSCR-1 knockoutマウスに敗血症shockを加えたところ、肺、心臓における炎症浸潤と心機能の低下に伴い、WTに比べ高い致死率を示すこと、逆にDSCR-1s強制発現マウスでは敗血症に強い抵抗性を示すことが明らかとなった(J.Clin. Invest)。一方、転写因子Egr-3はNFAT, SRF, CREBによって発現誘導され、NFATのメディエーターとして作用し、VEGF依存性の増殖、遊走、炎症、血管新生に必須の存在であること、そしてEgr-3発現を抑制することで血管新生、腫瘍増大が顕著に抑制されることを解明した(Blood)。また血管内皮特異的遺伝子発現において重要とされるGATA転写因子群のうち、大血管内皮で選択的に支配的に発現するGATA3がTie2発現制御に関わり、Ang1-Tie2を介する内皮遊走、抗アポトーシス、血管新生、抗炎症作用に密接に関与していることを明らかにした(J.Biol.Chem)。

Research Products

• [Journal Article] Vascular endothelial growth factor activation of endothelial cells is mediated by early growth response-3. (2010)
  • Author(s): Suehiro J, Hamakubo T, Kodama T, Aird WC, Minami T.
  • Journal Title: Blood Volume: 115 Pages: 2520-32
  • Peer Reviewed
• [Journal Article] The Down syndrome critical region gene 1 short variant promoters direct vascular bed-specific gene expression during inflammation in mice. (2009)
  • Author(s): Minami, T., Yano, K., Miura, M., Kobayashi, M., Suehiro, J-I., Reid, P.C., Hamakubo, T., Ryeom, S., Aird, W.C., Kodama T
  • Journal Title: J Clin Invest. Volume: 119 Pages: 2257-70
  • Peer Reviewed
• [Journal Article] Down's syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1. (2009)
  • Author(s): Baek KH, Zaslavsky A, Lynch RC, Britt C, Okada Y, Siarey RJ, Lensch MW, Park IH, Yoon SS, Minami T, Korenberg JR, Folkman J, Daley GQ, Aird WC, Galdzicki Z, Ryeom S.
  • Journal Title: Nature Volume: 459 Pages: 1126-30
  • Peer Reviewed
• [Journal Article] A critical role for GATA3 in mediating Tie2 expression and function in large vessel endothelial cells (2009)
  • Author(s): Song, H., Suehiro. J.I., Kanki, Y., Kawai, Y., Inoue, K., Daida, H., Yano, K., Ohashi, T., Ottegen. P., Aird, W.C., Kodama. T., Minami, T.
  • Journal Title: J Biol Chem. Volume: 284 Pages: 29109-29124
  • Peer Reviewed
• [Journal Article] Association of metastin/a G-protein-coupled receptor signaling and Down syndrome critical region 1 in epithelial ovarian cancer. (2009)
  • Author(s): Hata K, Watanabe Y, Nakai H, Minami T, Ohsaki H, Hirakawa E, Hoshiai H.
  • Journal Title: Anticancer Res. Volume: 29 Pages: 617-23
  • Peer Reviewed
• [Journal Article] Regulation of Down Syndrome Critical Region 1 expression by Nuclear Factor of Activated T cells in megakaryocytes. (2009)
  • Author(s): Kyttala S, Habermann I, Minami T, Ehninger G, Kiani A
  • Journal Title: Br J Haematol. Volume: 144 Pages: 395-408
  • Peer Reviewed
• [Journal Article] Differential roles for ETS, CREB and EGR binding sites in mediating VEGF receptor 1 expression in vivo (2009)
  • Author(s): Jin E, Liu J, Suehiro JI, Yuan L, Okada Y, Nikolova-Krstevski V, Yano K, Janes L, Beeler D, Spokes KC, Li D, Rcgan E, Shih SC, Oettgen P, Minami T, Aird WC.
  • Journal Title: Blood Volume: 114 Pages: 5557-66
  • Peer Reviewed
• [Journal Article] A +220 GATA motif mediates basal but not endotoxin-repressible expression of the von Willebrand factor promoter in Hprt-targeted transgenic mice (2009)
  • Author(s): Liu J, Kanki Y, Okada Y, Jin E, Yano K, Shih SC, Minami T, Aird WC
  • Journal Title: J Thromb Haemost. Volume: 7 Pages: 1384-92
  • Peer Reviewed
• [Journal Article] A wave of nascent transcription on activated human genes (2009)
  • Author(s): Wada Y, Ohta Y, Xu M, Tsutsumi S, Minami T, Inoue K, Komura D, Kitakami J, Oshida N, Papantonis A, Izumi A, Kobayashi M, Meguro H, Kanki Y, Mimura I, Yamamoto K, Mataki C, Hamakubo T, Shirahige K, Aburatani H, Kimura H, Kodama T, Cook PR, Ihara S.
  • Journal Title: Proc Natl Acad Sci USA. Volume: 106 Pages: 18357-61
  • Peer Reviewed
• [Journal Article] Angiopoietin-1 induces Kruppel-like factor 2 expression through a phosphoinositide 3-kinase/AKT-dependent activation of myocyte enhancer factor 2 (2009)
  • Author(s): Sako K, Fukuhara S, Minami T, Hamakubo T, Song H, Kodama T, Fukamizu A, Gutkind JS, Koh GY, Mochizuki N.
  • Journal Title: J Biol Chem. Volume: 284 Pages: 5592-601
  • Peer Reviewed
• [Journal Article] Angiopoietin-1 induces Kruppel-like factor 2 expression through a phos phoinositide 3-kinase/AKT-dependent activation of myocyte enhancer factor 2. (2009)
  • Author(s): Sako K, Fukuhara S, Minami T, Hamakubo T, Song H, Kodama T, Fukamizu A, Gutkind JS, Koh GY, Mochizuki N.
  • Journal Title: J Biol Chem 284 Pages: 5592-601
  • Peer Reviewed
• [Journal Article] Association of Matastin/a G-protein-coupled Receptor Signaling and Down Syndrome Critical Region 1 in Epithelial Ovarian Cancer (2009)
  • Author(s): Hata, K., Watanabe, Y., Nakai, H., Minami T, Ohsaki, H., Hirakawa, E.m Hoshiai, H.
  • Journal Title: Anticancer Research 29 Pages: 617-24
  • Peer Reviewed
• [Journal Article] Hepatocyte growth factor inhibits VEGF-forkhead-dependent gene expression in endothelial cells (2008)
  • Author(s): Abid MR, Nadeau RJ, Spokes KC, Minami T, Li D, Shih SC, Aird WC.
  • Journal Title: Arterioscler Thromb Vase Biol 28 Pages: 2042-8
  • Peer Reviewed
• [Journal Article] A GABP-binding element in the Robo4 promoter is necessary for endothelial expression in vivo (2008)
  • Author(s): Okada Y, Jin E, Nikolova-Krste vski V, Yano K, Liu J, Beeler D, Spokes K, Kitayama M, Funahashi N, Doi T, Janes L, Minami T, Oettgen P, Aird WC.
  • Journal Title: Blood 112 Pages: 2336-9
  • Peer Reviewed
• [Journal Article] Differential function of Tie2 at cell-cell contacts and cell-substratum contacts regulated by angiopoietin-1 (2008)
  • Author(s): Fukuhara, S., Sako, K., Minami, T., Noda, K., Kim, HZ., Kodama, T., Shibuya, M., Takakura, N., Koh, GY. And Mochizuki, N.
  • Journal Title: Nature Cell Biol 10 Pages: 513-26
  • Peer Reviewed
• [Presentation] Hprt-locus knock-in systemを用いた臓器血管内皮発現制御機構とVascular-bed heterogeneity (2009)
  • Author(s): 南敬
  • Organizer: 日本血管生物医学会
  • Place of Presentation: 東京大学安田講堂
  • Year and Date: 2009-10-09
• [Presentation] Vascular bed-specific down syndrome critical region-1 short isoform modulates sepsis morbidity and mortality (2009)
  • Author(s): Takashi Minami
  • Organizer: 7^<th> Japan-Korea Joint Symposium on Vascular Biology
  • Place of Presentation: Ewha Womans University, Korea
  • Year and Date: 2009-08-21
• [Presentation] Angiogenesis regulation via NFAT signaling in activated Endothelium (2008)
  • Author(s): Minami, T., Yano, K., Suehiro, J., Reid, P., Aird, WC., Kodama, T.
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2008-10-28
• [Presentation] Vascular-Bed Predominantly Expressed DSCR-1 Short Isoform At tenuates the Neo-angiogenesis and Inflammation (2008)
  • Author(s): Minami, T., Miura, M., Koba yashi, M., Reid, P., Aird, WC., Kodama, T.
  • Organizer: IVBM2008
  • Place of Presentation: Sydney, Australia
  • Year and Date: 2008-06-03
• [Remarks]
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• [Remarks]
  • URL: http://www.rcast.u-tokyo.ac.jp
• [Remarks]
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