Mechanisms for regulation of lymphangiogenesis

• Project/Area Number: 19209009
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: The University of Tokyo
• Principal Investigator: MIYAZONO Kohei The University of Tokyo, 大学院・医学系研究科, 教授 (90209908)
• Co-Investigator(Renkei-kenkyūsha): WATABE Tetsuro 東京大学, 大学院・医学系研究科, 准教授 (00334235) ; IWATA Caname 東京大学, 大学院・医学系研究科, 助教 (50511391)
• Project Period (FY): 2007 – 2009
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥49,530,000 (Direct Cost: ¥38,100,000、Indirect Cost: ¥11,430,000); Fiscal Year 2010: ¥12,090,000 (Direct Cost: ¥9,300,000、Indirect Cost: ¥2,790,000); Fiscal Year 2009: ¥12,090,000 (Direct Cost: ¥9,300,000、Indirect Cost: ¥2,790,000); Fiscal Year 2008: ¥12,090,000 (Direct Cost: ¥9,300,000、Indirect Cost: ¥2,790,000); Fiscal Year 2007: ¥13,260,000 (Direct Cost: ¥10,200,000、Indirect Cost: ¥3,060,000)
• Keywords: シグナル伝達 / 病理学 / 発生・分化 / 癌 / リンパ管新生 / 転写因子 / 転移 / 免疫 / シグナル亢進

Research Abstract

In order to elucidate the mechanisms of lymphangiogenesis, we have studied the action of Prox1, a master regulator of lymphangiogenesis. In this project, we have found that TGF-beta represses the expression Prox1, whereas HoxD8 induces it. In the nucleus, Prox1 was shown to interact with Ets family proteins and a nuclear receptor COUP-TFII to regulate expression of genes involved in lymphangiogenesis. We have also identified novel Prox1 target genes, including FoxC2, Ang-2, and HoxD8.

Research Products

• [Journal Article] Ets family members induce lymphangiogenesis via physical and functional interaction with Prox1 (2011)
  • Author(s): Yoshimatsu Y, Mihira H, Itoh T, Yuki K, Harada K, Morikawa M, Yamazaki T, Iwata C, Minami T, Morishita Y, Kodama T, Miyazono K, Watabe T
  • Journal Title: J Cell Sci. (掲載確定(印刷中))
  • Peer Reviewed
• [Journal Article] Ets family members induce lymphangiogenesis via physical and functional interaction with Prox1. (2011)
  • Author(s): Yoshimatsu, Y., et al.
  • Journal Title: Journal of Cell Science Volume: (掲載確定(印刷中))
  • Peer Reviewed
• [Journal Article] BMP-9 induces proliferation of multiple types of endothelial cells in vitro and in vivo. (2010)
  • Author(s): Suzuki Y, Ohga N, Morishita Y, Hida K, Miyazono K, Watabe T
  • Journal Title: J Cell Sci. 123(10) Pages: 1684-1692
  • Peer Reviewed
• [Journal Article] LPA4 regulates blood and lymphatic vessel formation during mouse embryogenesis. (2010)
  • Author(s): Sumida H, Noguchi K, Kihara Y, Abe M, Yanagida K, Hamano F, Sato S, Tamaki K, Morishita Y, Kano MR, Iwata C, Miyazono K, Sakimura K, Shimizu T, Ishii S.
  • Journal Title: Blood. 116(23) Pages: 5060-5070
  • Peer Reviewed
• [Journal Article] Inflammation induces lymphangiogenesis through up-regulation of VEGFR-3 mediated by NF-kappaB and Prox1. (2010)
  • Author(s): Flister MJ, Wilber A, Hall KL, Iwata C, Miyazono K, Nisato RE, Pepper MS, Zawieja DC, Ran S
  • Journal Title: Blood. 115(2) Pages: 418-429
  • Peer Reviewed
• [Journal Article] Inflammation induces lymphangiogenesis through up-regulation of VEGFR-3 mediated by NF-kappaB and Prox1 (2010)
  • Author(s): Flister MJ, Wilber A, Hall KL, Iwata C, Miyazono K, Nisato RE, Pepper MS, Zawieja DC, Ran S
  • Journal Title: Blood 115(2) Pages: 418-429
  • Peer Reviewed
• [Journal Article] LPA4 regulates blood and lymphatic vessel formation during mouse embryogenesis. (2010)
  • Author(s): Sumida, H, et al.
  • Journal Title: Blood Volume: 116 Pages: 5060-5070
  • Peer Reviewed
• [Journal Article] Inflammation induces lymphangiogenesis through up-regulation of VEGFR-3 mediated by NF-κB and Prox1 (2010)
  • Author(s): Flister, M.J., et al.
  • Journal Title: Blood Volume: 115 Pages: 418-429
  • Peer Reviewed
• [Journal Article] BMP-9 induces proliferation of multiple types of endothelial cells in vitro and in vivo. (2010)
  • Author(s): Suzuki, Y., et al.
  • Journal Title: Journal of Cell Science Volume: 123 Pages: 1684-1692
  • Peer Reviewed
• [Journal Article] Identification of Prox1 targets during in vitro vascular differentiation from embryonic stem cells : functional roles of HoxD8 in lymphangiogenesis. (2009)
  • Author(s): Harada K, Yamazaki T, Iwata C, Yoshimatsu Y, Sase H, Mishima K, Morishita Y, Hirashima M, Oike Y, Suda T, Miura N, Watabe T, Miyazono K
  • Journal Title: J Cell Sci. 122(21) Pages: 3923-3930
  • Peer Reviewed
• [Journal Article] VEGFR2-PLCgamma1 axis is essential for endothelial specification of VEGFR2+ vascular progenitor cells. (2009)
  • Author(s): Sase H, Watabe T, Kawasaki K, Miyazono K, Miyazawa K
  • Journal Title: J Cell Sci. 122(18) Pages: 3303-3311
  • Peer Reviewed
• [Journal Article] COUP-TFII regulates the functions of Prox1 in lymphatic endothelial cells through direct interaction. (2009)
  • Author(s): Yamazaki T, Yoshimatsu Y, Morishita Y, Miyazono K, Watabe T
  • Journal Title: Genes Cells 14(3) Pages: 425-434
  • Peer Reviewed
• [Journal Article] Identification of Prox1 targets during in vitro vascular differentiation from embryonic stem cells : functional roles of HoxD8 in lymphangiogenesis (2009)
  • Author(s): Harada K, Yamazaki T, Iwata C, Yoshimatsu Y, Sase H, Mishima K, Morishita Y, Hirashima M, Oike Y, Suda T, Miura N, Watabe T, Miyazono K
  • Journal Title: J Cell Sci. 122(21) Pages: 3923-3930
  • Peer Reviewed
• [Journal Article] COUP-TFII regulates the functions of Prox1 in lymphatic endothelial cells through direct interaction (2009)
  • Author(s): Yamazaki T, Yoshimatsu Y, Morishita Y, Miyazono K, Watabe T
  • Journal Title: Genes Cells 14(3) Pages: 425-434
  • Peer Reviewed
• [Journal Article] VEGFR2-PLCγ1 axis is essential for endothelial specification of VEGFR2+ vascular progenitor cells (2009)
  • Author(s): Sase, H., et al.
  • Journal Title: Journal of Cell Science Volume: 122 Pages: 3303-3311
  • Peer Reviewed
• [Journal Article] Identification of targets of Prox1 during in vitro vascular differentiation from embryonic stem cells : functional roles of HoxD8 in lymphangiogenesis (2009)
  • Author(s): Harada, K., et al.
  • Journal Title: Journal of Cell Science Volume: 122 Pages: 3923-3930
  • Peer Reviewed
• [Journal Article] COUP-TFII regulates the functions of Prox1 in lymphatic endothelial cells through direct interaction (2009)
  • Author(s): Tamazaki, T. , et. al
  • Journal Title: Genes to Cells 4 Pages: 425-434
  • Peer Reviewed
• [Journal Article] Inhibition of endogenous TGF-beta signaling enhances lymphangiogenesis. (2008)
  • Author(s): Oka M, Iwata C, Suzuki HI, Kiyono K, Morishita Y, Watabe T, Komuro A, Kano MR, Miyazono K
  • Journal Title: Blood. 111(9) Pages: 4571-4579
  • Peer Reviewed
• [Journal Article] Inhibition of endogenous TGF-beta signaling enhances lymphangiogenesis (2008)
  • Author(s): Oka M, Iwata C, Suzuki HI, Kiyono K, Morishita Y, Watabe T, Komuro A, Kano MR, Miyazono K
  • Journal Title: Blood 111(9) Pages: 4571-4579
  • Peer Reviewed
• [Journal Article] Inhibition of endogenous TGF-β signaling enhances lymphangiogenesis (2008)
  • Author(s): Oka, M. , et. al
  • Journal Title: Blood 11 Pages: 4571-4579
  • Peer Reviewed
• [Journal Article] Inhibition of endogenous TGF-β signaling enhances lymphangiogenesis (2008)
  • Author(s): Oka, M., et. al.
  • Journal Title: Blood (掲載確定)
  • Peer Reviewed
• [Journal Article] Inhibition of cyclooxygenase-2 suppresses lymph node metastasis via reduction of lymphangiogenesis. (2007)
  • Author(s): Iwata C, Kano MR, Komuro A, Oka M, Kiyono K, Johansson E, Morishita Y, Yashiro M, Hirakawa K, Kaminishi M, Miyazono K
  • Journal Title: Cancer Res. 67(21) Pages: 10181-10189
  • Peer Reviewed
• [Journal Article] Inhibition of cyclooxygenase-2 suppresses lymph node metastasis via reduction of lymphangiogenesis (2007)
  • Author(s): Iwata C, Kano MR, Komuro A, Oka M, Kiyono K, Johansson E, Morishita Y, Yashiro M, Hirakawa K, Kaminishi M, Miyazono K
  • Journal Title: Cancer Res. 67(21) Pages: 10181-101819
  • Peer Reviewed
• [Journal Article] Inhibition of cyclooxygenase-2 suppresses lymph node metastasis via reduction of lymphangiogenesis (2007)
  • Author(s): Iwata, C., et. al.
  • Journal Title: Cancer Research 67 Pages: 10181-10189
  • Peer Reviewed
• [Presentation] Prox1結合因子であるEts-2のリンパ管新生における役割 (2009)
  • Author(s): 吉松康裕、他
  • Organizer: 第17回日本血管生物医学会
  • Place of Presentation: 東京・東京大学安田講堂
  • Year and Date: 2009-10-09
• [Presentation] BMP-9はALK-1を介して胚性幹細胞由来血管内皮細胞の増殖を亢進する (2009)
  • Author(s): 鈴木夕佳、他
  • Organizer: 第17回日本血管生物医学会
  • Place of Presentation: 東京・東京大学安田講堂
  • Year and Date: 2009-10-09
• [Presentation] Prox1結合因子であるEts-2のリンパ管新生における役割 (2009)
  • Author(s): 吉松康裕, 他
  • Organizer: 第17回日本血管生物医学会
  • Place of Presentation: 東京大学安田講堂(東京都文京区)
  • Year and Date: 2009-10-09
• [Presentation] BMP-9はALK-1を介して胚性幹細胞由来血管内皮細胞の増殖を亢進する (2009)
  • Author(s): 鈴木夕佳, 他
  • Organizer: 第17回日本血管生物医学会
  • Place of Presentation: 東京大学安田講堂(東京都文京区)
  • Year and Date: 2009-10-09
• [Presentation] Microstructural changes of lymphatic endothelium in metastatic lymph node. (2009)
  • Author(s): Iwata C, 他
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: 横浜・パシフィコ横浜
  • Year and Date: 2009-10-03
• [Presentation] Microstructural changes of lymphatic endothelium in metastatic lymphnode (2009)
  • Author(s): Iwata, C., et al.
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: 横浜パシフィコ(神奈川県横浜市)
  • Year and Date: 2009-10-03
• [Presentation] COUP-TFII regulates the functions of Prox1 in lymphatic endothelial cells through direct interaction. (2008)
  • Author(s): Yamazaki T, 他
  • Organizer: 第16回日本血管生物医学会
  • Place of Presentation: 金沢・石川県立音楽堂交流ホール
  • Year and Date: 2008-12-03
• [Presentation] Functional roles of HoxD8 during lymphangiogenesis. (2008)
  • Author(s): Harada K, et al.
  • Organizer: 第16回日本血管生物医学会
  • Place of Presentation: 金沢・石川県立音楽堂交流ホール
  • Year and Date: 2008-12-03
• [Presentation] Snail is required for TGF-β-induced endothelial-mesenchymal transition of embryonic stem cell-derived endothelial cells. (2008)
  • Author(s): Watabe T, 他
  • Organizer: 第16回日本血管生物医学会
  • Place of Presentation: 金沢・石川県立音楽堂交流ホール
  • Year and Date: 2008-12-03
• [Presentation] リンパ管新生におけるHoxD8及びHoxD9の機能 (2008)
  • Author(s): 原田香織、他
  • Organizer: 第60回日本細胞生物学会大会
  • Place of Presentation: 横浜・パシフィコ横浜
  • Year and Date: 2008-07-01
• [Presentation] Roles of Ets family members in the regulation of Prox1-mediated lymphatic differentiation of endothelial cells. (2008)
  • Author(s): Watabe T, 他
  • Organizer: The 15th International Vascular Biology Meeting.
  • Place of Presentation: オーストラリア、シドニー・Sydney Convention & Exhibition Centre
  • Year and Date: 2008-06-04
• [Presentation] Roles of Ets family members in the regulation of Proz1-mediated lymphatic differentiation of endothelial sells (2008)
  • Author(s): Watabe, T. , et al.
  • Organizer: The 15th International Vascular Biology Meeting
  • Place of Presentation: Sydney, Australia-Sydney Convention & Exhibition Centre
  • Year and Date: 2008-06-04
• [Presentation] Regulation of angiogenesis and lymphangiogenesis by TGF-βsignaling (2008)
  • Author(s): Miyazono, K.
  • Organizer: The U.S.-Japan Cooperative Cancer Research Program Workshop
  • Place of Presentation: 京都
  • Year and Date: 2008-03-19
• [Presentation] Roles of ALK-1 in BMP-9-induced proliferation of mouse embryonic stem cell derived endothelial cells (2008)
  • Author(s): Suzuki Y. , et al.
  • Organizer: 第16回日本血管生物医学会
  • Place of Presentation: 金沢・石川県立音楽堂交流ホール
• [Presentation] Ets transcription factors Ets-1and-2 positively regulate Prox1 during lymphangiogenesis (2008)
  • Author(s): Yoshimatsu Y. , et al.
  • Organizer: 第16回日本血管生物医学会
  • Place of Presentation: 金沢・石川県立音楽堂交流ホール
• [Presentation] Functional roles of HoxD8 during lymphangiogenesis (2008)
  • Author(s): Harada k. , et al.
  • Organizer: 第16回日本血管生物医学会
  • Place of Presentation: 金沢・石川県立音楽堂交流ホール
• [Presentation] Shail is required for TGF-β-induced endothelial-mesenchymal transition of embryonic stem cell-derived endothelial cells (2008)
  • Author(s): Watabe, T. , et al.
  • Organizer: 第16回日本血管生物医学会
  • Place of Presentation: 金沢・石川県立音楽堂交流ホール
• [Presentation] COUP-TFII regulates the functions of Prox1 in lymphatic endothelial cells through direct interaction (2008)
  • Author(s): Yamazaki t. , et al.
  • Organizer: 第16回日本血管生物医学会
  • Place of Presentation: 金沢・石川県立音楽堂交流ホール
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