Analysis of cellular signals toward carcinogenesis and metastasis using genetically modified mice

• Project/Area Number: 20012027
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Kyoto University
• Principal Investigator: TAKAHASHI Chiaki Kyoto University, がん研究所, 教授 (50283619)
• Co-Investigator(Renkei-kenkyūsha): SHAMMA Awad 金沢大学, がん研究所, 助教 (50402839)
• Project Period (FY): 2008 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥18,000,000 (Direct Cost: ¥18,000,000); Fiscal Year 2009: ¥9,000,000 (Direct Cost: ¥9,000,000); Fiscal Year 2008: ¥9,000,000 (Direct Cost: ¥9,000,000)
• Keywords: がん / がん抑制遺伝子 / がん遺伝子 / 細胞老化 / DNA損傷 / Rb / Ras / 悪性化 / クロマチンリモデリング / がん幹細胞 / セネセンス / DNA損傷応答 / 前がん病変 / イソプレニル化

Research Abstract

We analyzed Rb-heterozygous mice simultaneously lacking various Rb-related genes. We proved that Rb-deficient carcinogenesis is antagonized by cellular senescence and DNA damage response in a Ras-dependent manner. We also discovered that Rb inactivation upregulates number of genes involved in protein isoprenylation via E2F or SREBP leading to accelerated membrane trafficking of Ras. In addition, we discovered that RECK, an antagonistic downstream target of Ras, regulates beta1-integrin and EGFR signaling.

Research Products

• [Journal Article] The・β1-integrin-dependent function of RECK in physiologic and tumor angiogenesis (2010)
  • Author(s): T. Miki, A. Shamma, S. Kitajima, Y. Takegami, M. Noda, Y. Nakashima, K. Watanabe, C. Takahashi
  • Journal Title: Mol. Cancer Res.
  • NAID: 120002224338
  • Peer Reviewed
• [Journal Article] Hypoxia and RAS signaling pathways converge on, and cooperatively down-regulate, the RECK tumor suppressor protein via microRNAs. (2010)
  • Author(s): F. Loayza-Puch, Y. Yoshida, T. Matsuzaki, C. Takahashi, H. Kitayama, M. Noda.
  • Journal Title: Oncogene
  • Peer Reviewed
• [Journal Article] The β1-integrin-dependent function of RECK in physiologic and tumor angiogenesis. (2010)
  • Author(s): T.Miki, A.Shamma, S.Kitajima, Y.Takegami, M.Noda, Y.Nakashima, K.Watanabe, C.Takahashi.
  • Journal Title: Mol.Cancer Res. (印刷中)
  • NAID: 120002224338
  • Peer Reviewed
• [Journal Article] Hypoxia and RAS signaling pathways converge on, and cooperatively down-regulate, the RECK tumor suppressor protein via microRNAs. (2010)
  • Author(s): F.Loayza-Puch, Y.Yoshida, T.Matsuzaki, C.Takahashi, H.Kitayama, M.Noda.
  • Journal Title: Oncogene
  • Peer Reviewed
• [Journal Article] Rb regulates DNA damage response and cellular senescence through E2F-dependent suppression of N-Ras Isoprenylation. (2009)
  • Author(s): A. Shamma, Y. Takegami, T. Miki, S. Kitajima, M. Noda, T. Obara, T. Okamoto, C. Takahashi
  • Journal Title: Cancer Cell 15 Pages: 255-269
  • NAID: 120001546496
  • Peer Reviewed
• [Journal Article] RECK forms cowbell-shaped dimmers and inhibits MMP-catalyzed cleavage of fibronectin. (2009)
  • Author(s): A. Omura, T Matsuzaki, K. Miio, T. Ogura, M. Yamamoto, A. Fujita, K. Okawa, H. Kitayama, C. Takahashi, C. Sato, M. Noda.
  • Journal Title: J. Biol. Chem. 284 Pages: 3461-3169
  • Peer Reviewed
• [Journal Article] Rb regulates DNA damage response and cellular senescence through E2F-dependent suppression of N-Ras Isoprenylation. (2009)
  • Author(s): A.Shamma, Y.Takegami, T.Miki, S.Kitajima, M.Noda, T.Obara, T.Okamoto, C.Takahashi.
  • Journal Title: Cancer Cell 15 Pages: 255-269
  • NAID: 120001546496
  • Peer Reviewed
• [Journal Article] RECK forms cowbell-shaped dimmers and inhibits MMP-catalyzed cleavage of fibronectin. (2009)
  • Author(s): A.Omura, T.Matsuzaki, K.Miio, T.Ogura, M.Yamamoto, A.Fujita, K.Okawa, H.Kitayama, C.Takahashi, C.Sato, M.Noda.
  • Journal Title: J.Biol. Chem. 284 Pages: 3461-3169
  • Peer Reviewed
• [Journal Article] Regulation of Notch signaling and its polarity mediated by ectodomain shedding of DSL ligands. (2009)
  • Author(s): C.Takahashi, T.Muraguchi, Y.Takegami, T.Miki.
  • Journal Title: Tanpakushitsu Kakusan Koso (in Japanese) 54(13) Pages: 1742-1746
  • NAID: 40016835263
• [Journal Article] The genetic and biochemical interactions of Rb and ras. (2009)
  • Author(s): C.Takahashi, Y.Takegami, A.Shamma.
  • Journal Title: Seikagaku (in Japanese) 81(10) Pages: 873-883
  • NAID: 10026298655
• [Journal Article] Rb regulates DNA damage response and cellular senescence through E2F-dependent suppression of N-Ras Isoprenylation (2009)
  • Author(s): A. Shamma, Y. Takegami, T, Miki, S. Kitajima, M. Noda, T. Ohara, T. Okamoto and C. Takahashi
  • Journal Title: Cancer Cell 15
  • NAID: 120001546496
  • Peer Reviewed
• [Journal Article] RECK forms cowbell-shaped dimmers and inhibits MMP-catalyzed cleavage of fibronectin (2009)
  • Author(s): A. Omura, T Matsuzaki, K. Milo, T. Ogura, M. Yamamoto, A. Fujita, K. Okawa, H. Kitayama, C. Takahashi, C. Sato and M. Nods
  • Journal Title: J. Biol. Chem 284 Pages: 3461-3469
  • Peer Reviewed
• [Journal Article] Localization of the membrane-anchored MMP-regulator RECK at the neuromuscular junctions. (2008)
  • Author(s): S. Kawashima, T. Noda, E. Chandana, Y. Imamura, R. Takahashi, E. Adachi, C. Takahashi, M. Noda
  • Journal Title: J. Neurochem. 104 Pages: 376-385
  • Peer Reviewed
• [Journal Article] Localization of the membrane-anchored MMP-regulator RECK at the neuromuscular junctions (2008)
  • Author(s): S. Kawashima, T. Noda, E. Chandana, Y. Imamura, R. Takahashi, E. Adachi, C. Takahashi and M. Noda
  • Journal Title: J. Neurochem 104 Pages: 376-385
  • Peer Reviewed
• [Presentation] The Rb-Ras pathway in malignant progression (2010)
  • Author(s): C. Takahashi.
  • Organizer: National Sun Yat-Sen University International Cancer Biology Symposium
  • Place of Presentation: National Sun Yat-Sen University (Taiwan)
  • Year and Date: 2010-06-27
• [Presentation] RECK regulates p53-p21-dependent cellular senescence in mouse embryonic fibroblasts. (2009)
  • Author(s): S. Kitajima, T. Miki, C. Takahash.
  • Organizer: 日本分子生物学会年会ポスター発表
  • Place of Presentation: 日パシフィコ横浜(神奈川県)
  • Year and Date: 2009-12-12
• [Presentation] RECK regulates p53-p21-dependent cellular senescence in mouse embryonic fibroblasts (2009)
  • Author(s): S.Kitajima, T.Miki, C.Takahashi
  • Organizer: 日本分子生物学会年会ポスター発表
  • Place of Presentation: パシフィコ横浜(神奈川)
  • Year and Date: 2009-12-12
• [Presentation] The genetic interaction of Rb and ras unveiled by the study of compound knockout mice. (2009)
  • Author(s): C. Takahashi, Y. Takegami, T. Miki, S. Kitajima, A. Shamma
  • Organizer: 日本生化学会大会シンポジウム
  • Place of Presentation: 神戸国際会議場(兵庫県)
  • Year and Date: 2009-10-22
• [Presentation] The genetic interaction of Rb and ras unveiled by the study of compound knockout mice (2009)
  • Author(s): C.Takahashi, Yujiro Takegami, Takao Miki, Shunsuke Kitajima, A.Shamma
  • Organizer: 日本生化学会大会シンポジウム
  • Place of Presentation: 神戸国際会議場(兵庫)
  • Year and Date: 2009-10-22
• [Presentation] Critical role of cellular senescence mediated by N-Ras isoprenylation in suppressing Rb-deficient C-cell carcinogenesis (2009)
  • Author(s): A. Shamma, C. Takahashi
  • Organizer: 日本癌学会総会口頭発表
  • Place of Presentation: 神戸国際会議場(兵庫)
  • Year and Date: 2009-10-02
• [Presentation] Critical role of cellular senescence mediated by N-Ras isoprenylation in suppressing Rb-deficient C-cell carcinogenesis (2009)
  • Author(s): A.Shamma, C.Takahashi
  • Organizer: 日本癌学会総会口頭発表
  • Place of Presentation: パシフィコ横浜(神奈川)
  • Year and Date: 2009-10-02
• [Presentation] The genetic interaction of Rb and ras in the multi-step carcinogenesis model (2009)
  • Author(s): C. Takahashi, A. Shamma
  • Organizer: 癌学会総会シンポジウム
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2009-10-01
• [Presentation] Regulation of Notch signaling and its polarity mediated by ectodomain shedding of DSL ligands. (2009)
  • Author(s): C.Takahashi, T.Muraguchi, Y.Takegami, T.Miki.
  • Organizer: 日本癌学会総会シンポジウム
  • Place of Presentation: パシフィコ横浜(神奈川)
  • Year and Date: 2009-10-01
• [Presentation] RECKによるp21CIP1依存的な細胞増殖・細胞老化の制御 (2009)
  • Author(s): 北嶋俊輔, 三木高雄, 高橋智聡
  • Organizer: 日本病態プロテアーゼ学会ポスター発表
  • Place of Presentation: 千里ライフサイエンスセンター(大阪)
  • Year and Date: 2009-08-21
• [Presentation] RECKによるp21CIP1依存的な細胞増殖・細胞老化の制御 (2009)
  • Author(s): 北嶋俊輔、三木高雄、高橋智聡
  • Organizer: 日本病態プロアテーゼ学会ボスター発表
  • Place of Presentation: 千里ライフサイエンスセンター(大阪)
  • Year and Date: 2009-08-21
• [Presentation] The function and mechanism of pRb-N-Ras pathway in metastatic conversion of neuroendocrine thyroid tumor (2009)
  • Author(s): C. Takahashi, A. Shamma
  • Organizer: Korean Society for Biochemistry and Molecular Biology (KSBMB)シンポジウム
  • Place of Presentation: COEX (Korea)
  • Year and Date: 2009-05-13
• [Presentation] The function and mechanism of pRb-N-Ras pathway in metastatic conversion of neuroendocrine thyroid tumor. (2009)
  • Author(s): C.Takahashi, A.Shamma
  • Organizer: Korean Society for Biochemistry and Molecular Biology (KSBMB)シンポジウム
  • Place of Presentation: COEX (Seoul, Korea)
  • Year and Date: 2009-05-13
• [Presentation] RECKによる膜結合型メタロプロテアーゼ群の制御 (2008)
  • Author(s): 高橋智聡, 三木貴雄, 村口輝行, 竹上雄治郎, 北嶋俊輔
  • Organizer: 日本分子生物学会・生化学学会合同年会BMB2008シンポジウム
  • Place of Presentation: 神戸国際会議場(兵庫県)
  • Year and Date: 2008-12-10
• [Presentation] RECKによる膜結合型メタロプロテアーゼ群の制御 (2008)
  • Author(s): 高橋智聡、三木貴雄、村口輝行、竹上雄治郎、北嶋俊輔
  • Organizer: 日本分子生物学会・生化学学会合同年会BMB2008シンポジウム
  • Place of Presentation: 神戸・ポートビアアイランド
  • Year and Date: 2008-12-10
• [Presentation] RECK regulates Notch signaling during cortical development by directly interacting with ADAM10 (2008)
  • Author(s): T. Muraguchi, Y. Takegami, T. Miki, S. Kitajima, C. Takahashi
  • Organizer: 細胞生物学会ミニシンポジウム
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2008-06-29
• [Presentation] RECK .regulates Notch signaling during cortical development by directly interacting with ADAM10 (2008)
  • Author(s): T. Muraguchi, Y. Takegami, T. Miki, S. Kitajima and C. Takahashi
  • Organizer: 細胞生物学会ミニシンポジウム
  • Place of Presentation: 横浜・みなとみらい
  • Year and Date: 2008-06-29
• [Book] Regulation of Notch signaling and its polarity mediated by ectodomain shedding of DSL ligands.(Tanpakushitsu Kakusan Koso(in Japanesse)Oct; 54(13)) (2009)
  • Author(s): C. Takahashi, T. Muraguchi, Y. Takegami, T. Miki.
• [Book] The genetic and biochemical interactions of Rb and ras.(Seikagaku(in Japanese)Oct;81(10)) (2009)
  • Author(s): C. Takahashi, Y. Takegami, A. Shamma
• [Remarks]
  • URL: http://web.me.com/takahashichiaki/
• [Remarks]
  • URL: http://www.kanazawa-u.ac.jp/~ganken/index.html
• [Remarks]
  • URL: http://bisei15.mb.med.kyoto-u.ac.jp/medcoe/member/tokunin/takahashi.html