Molecular mechanism of DNA damage-induced responses and its failure by carcinogenesis

2009 Fiscal Year Final Research Report

• Project/Area Number: 17014062
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Kobe University
• Principal Investigator: MINAMI Yasuhiro Kobe University, 大学院・医学研究科, 教授 (70229772)
• Co-Investigator(Kenkyū-buntansha): YODA AKINORI 神戸大学, 大学院・医学研究科, 助教 (70335454) ; NISHITA MICHIRU 神戸大学, 大学院・医学研究科, 准教授 (30379359) ; ENDO MITSUHARU 神戸大学, 大学院・医学研究科, 助教 (90436444) ; YAMAGATA KAORU 神戸大学, 大学院・医学研究科, 助教 (80533786)
• Project Period (FY): 2005 – 2009
• Keywords: DNA損傷応答 / シグナル伝達 / がん化 / Chk2キナーゼ / Wip1ホスファターゼ / Wnt5a / Ror2シグナル / がんの浸潤

Research Abstract

It has been shown that following DNA damage anti-oncogenic protein kinases, including ATM, Chk1 and Chk2 kinases, are phosphorylated and activated, thereby executing checkpoint machinery, leading to cell-cycle arrest. Subsequently, oncogenic Wip1 phosphatase are induced by p53, and dephosphorylates and inactivates phosphorylated -protein kinases, thereby re-starts arrested cell-cycle. In addition, we have shown that in osteosarcoma cell lines constitutively active Wnt5a/Ror2 signaling induces matrix metalloproteinase-13, thereby confers invasive properties on osteosarcoma cells.

Research Products

• [Journal Article] Cell/tissue-tropic functions of Wnt5a signaling in normal and cancer cells (2010)
  • Author(s): Nishita, M., Enomoto, M., Yamagata, K., Minami, Y.
  • Journal Title: Trends in Cell Biol 20 Pages: 346-354
  • Peer Reviewed
• [Journal Article] Ror2 is required for midgut elongation during mouse development. (2010)
  • Author(s): amada, M., Udagawa, J., Matsumoto, A., Hashimoto, R., Nishita, M., Minami, Y., Otani, H.
  • Journal Title: Dev. Dyn. 239 Pages: 941-953
  • Peer Reviewed
• [Journal Article] The Ror-family receptor tyrosine kinases in non-canonical Wnt signaling: Their implications in developmental morphogenesis and human diseases. (2010)
  • Author(s): Minami, Y., Oishi, I., Endo, M., Nishita, M.
  • Journal Title: Dev. Dyn. 239 Pages: 1-15
  • Peer Reviewed
• [Journal Article] The Ror2 receptor requires tyrosine kinase activity to mediate Wnt5a signaling. (2009)
  • Author(s): Mikels, A., Minami, Y., Nusse, R.
  • Journal Title: J. Biol. Chem. 284 Pages: 30167-30176
  • Peer Reviewed
• [Journal Article] Autonomous regulation of osteosarcoma cell invasiveness by Wnt5a/Ror2 signaling (2009)
  • Author(s): Enomoto, M., Hayakawa, S., Itsukushima, S., Dayong, R., Matsuo, M., Tamada, K., Oneyama, C., Okada, M., Takumi, T., Nishita, M., Minami, Y.
  • Journal Title: Oncogene 28 Pages: 3197-3208
  • Peer Reviewed
• [Journal Article] Wnt5a regulates directional cell migration and cell proliferation via the Ror2-mediated noncanonical pathway in mammalian palate development. (2008)
  • Author(s): He, F., Xiong, W., Yu, X., Espinoza, R., Liu, C., Nishita, M., Yamada, G., Minami, Y., Chen, Y.
  • Journal Title: Development 135 Pages: 3871-3879
  • Peer Reviewed
• [Journal Article] Receptor tyrosine kinase Ror2 mediates Wnt5a-induced polarized cell migration by activating c-Jun N-terminal kinase via actin-binding protein filamin A. (2008)
  • Author(s): Nomachi, A., Nishita, M., Inaba, D., Enomoto, M., Hamasaki, M., Minami, Y.
  • Journal Title: J. Biol. Chem. 283 Pages: 27973-27981
  • Peer Reviewed
• [Journal Article] Arsenic trioxide augments Chk2/p53-mediated apoptosis by inhibiting oncogenic Wip1 phosphatase. (2008)
  • Author(s): Yoda, A., Toyoshima, K., Watanabe, Y., Onishi, N., Hasaka, Y., Tsukuda, Y., Tsukada, J., Kondo, T., Tanaka, Y., Minami, Y.
  • Journal Title: J. Biol. Chem. 283 Pages: 18969-18979
  • Peer Reviewed
• [Journal Article] Cthrc1 selectively activates planar cell polarity pathway of Wnt signaling by stabilizing Wnt-receptor complex (2008)
  • Author(s): Yamamoto, S., Nishimura, O., Misaki, K., Nishita, M., Minami, Y., Yonemura, S., Tarui, H., Sasaki, H.
  • Journal Title: Dev. Cell 15 Pages: 23-36
  • Peer Reviewed
• [Journal Article] Chk2 kinase is required for methylglyoxal-induced G2/M cell-cycle checkpoint arrest: implication of cell-cycle checkpoint regulation in diabetic oxidative stress signaling. (2007)
  • Author(s): Kani, S., Nakayama, E., Yoda, A., Onishi, N., Sougawa, N., Hazaka, Y., Umeda, T., Takeda, K., Ichijo, H., Hamada, Y., Minami, Y.
  • Journal Title: Genes Cells 12 Pages: 919-928
  • Peer Reviewed
• [Journal Article] Filopodia formation mediated by receptor tyrosine kinase Ror2 is required for Wnt5a-induced cell migration. (2006)
  • Author(s): Nishita, M., Yoo, S-K., Nomachi, A., Kani, S., Sougawa, N., Ohta, Y., Takada, S., Kikuchi, A., Minami, Y.
  • Journal Title: J. Cell. Biol. 175 Pages: 555-562
  • Peer Reviewed
• [Journal Article] Wip1 phosphatase modulates ATM-dependent signaling pathways (2006)
  • Author(s): Shreeram, S., Demidov, O.N., Hee, W.K., Yamaguchi, H., Onishi, N., Kek, C., Timofeev, O.N., Dudgeon, C., Fornace, A.J., Anderson, C.W., Minami, Y., Appella, E., Bulavin, D.V.
  • Journal Title: Mol. Cell 23 Pages: 757-764
  • Peer Reviewed
• [Journal Article] Intrinsic kinase activity and SQ/TQ cluster domain of Chk2 kinase as well as N-terminal domain of Wip1 phosphatase are required for regulation of Chk2 by Wip1 (2006)
  • Author(s): Yoda, A., Xu, X.Z., Fujimoto, H., Kato, N., Onishi, N., Oishi, I., Minami, Y.
  • Journal Title: J. Biol. Chem. 281 Pages: 24847-24862
  • Peer Reviewed
• [Journal Article] Regulation of the anti-oncogenic Chk2 kinase by the oncogenic Wip1 phosphatase. (2006)
  • Author(s): Fujimoto, H., Onishi, N., Kato, N., Takekawa, M., Xu, X.Z., Kosugi, A., Kondo, T., Oishi, I., Yoda, A., Imamura, M., Minami, Y.
  • Journal Title: Cell Death Differ. 13 Pages: 1170-1180
  • Peer Reviewed
• [Presentation] Wnt5a-Ror2シグナルによる細胞極性・移動制御とがんの浸潤 (2010)
  • Author(s): 南康博
  • Organizer: 第62回日本細胞生物学会大会(ミニシンポジウム)
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2010-05-20
• [Presentation] Wnt5a・Ror2受容体チロシンキナーゼによる細胞極性・移動制御におけるタンパク質リン酸化の役割 (2009)
  • Author(s): 南康博
  • Organizer: 第82回日本生化学会大会(シンポジウム)
  • Place of Presentation: 神戸ポートアイランド国際会議場
  • Year and Date: 2009-10-21
• [Presentation] Wnt5a/Ror2シグナルによる細胞運動制御 (2008)
  • Author(s): 西田満、南康博
  • Organizer: 第31回日本分子生物学会年会・第81回日本生化学会大会合同大会(シンポジウム)
  • Place of Presentation: 神戸ポートピアホテル
  • Year and Date: 2008-12-12
• [Presentation] Role of Ror2 receptor tyrosine kinase and its in invasion and metastasis of osteosarcoma cells (2008)
  • Author(s): Yasuhiro Minami
  • Organizer: 2nd The Japn-Korea Joint Meeting on Wnt signaling and human diseases
  • Place of Presentation: Hiroshima Univ. Hiroshima
  • Year and Date: 2008-11-21
• [Presentation] Ror2 receptor tyrosine kinase and its implication in human diseases (2007)
  • Author(s): Yasuhiro Minami
  • Organizer: 1st The Japn-Korea Joint Meeting on Wnt signaling and human diseases
  • Place of Presentation: Yonsei Univ. Korea
  • Year and Date: 2007-10-26
• [Presentation] DNA損傷に伴う細胞周期チェックポイントの作動・解除及びアポトーシスの制御機構とがんの分子標的治療への応用 (2005)
  • Author(s): 南康博
  • Organizer: 第64回日本癌学会学術総会(シンポジウム)
  • Place of Presentation: ロイトン札幌
  • Year and Date: 2005-06-15
• [Book] イラストレイテッド生化学原著4版"Lippincott's Illustrated Reviews: Biochemistry 4th ed. (石崎泰樹、丸山敬 監訳) (2008)
  • Author(s): 西田満、依田成玄、南康博
  • Publisher: 丸善(株)出版
• [Remarks]
  • URL: http://www.med.kobe-u.ac.jp/medzoo/