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Molecular mechanism for cell-cell adhesion in canceration and metastasis

Research Project

Project/Area Number 12219210
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionKYOTO UNIVERSITY

Principal Investigator

TSUKITA Shoichiro  Kyoto University, Graduate School of Medicine, Professor, 医学系研究科, 教授 (50155347)

Co-Investigator(Kenkyū-buntansha) FURUSE Mikio  Kyoto University, Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (90281089)
KUBO Akiharu  Kyoto University, Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (70335256)
ADACHI Makoto  Kyoto University, Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (30335244)
TSUKITA Sachiko  Kyoto University, Faculty of Medicine, Professor, 医学部, 教授 (00188517)
佐々木 博之  東京慈恵会医科大学, DNA研究所, 講師 (60170693)
伊藤 雅彦  京都大学, 医学研究科, 助手 (70270486)
米村 重信  京都大学, 医学研究科, 講師 (60192811)
永渕 昭良  熊本大学, 発生医学研究センター, 教授 (80218023)
Project Period (FY) 2000 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥443,900,000 (Direct Cost: ¥443,900,000)
Fiscal Year 2004: ¥89,500,000 (Direct Cost: ¥89,500,000)
Fiscal Year 2003: ¥89,500,000 (Direct Cost: ¥89,500,000)
Fiscal Year 2002: ¥89,500,000 (Direct Cost: ¥89,500,000)
Fiscal Year 2001: ¥89,000,000 (Direct Cost: ¥89,000,000)
Fiscal Year 2000: ¥86,400,000 (Direct Cost: ¥86,400,000)
Keywordscell-cell adhesion / tight junction / claudin / occludin / ERM proteins / epidermal barrier / knockout mouse / cell proliferation / Snail / ZO-1 / ZO-2 / がん / 上皮間葉転換 / 転移浸潤 / GFP / ドラッグデリバリー / ノックアウト / 上皮細胞 / 血液脳関門 / メルリン / MUPP1 / PDZドメイン / 大腸癌 / ラディキシン / α-カテニン / β-カテニン / ERM / アドヘレンスジャンクション / カドヘリン
Research Abstract

More than 90% of malignant tumors are derived from the epithelium. Thus, in this project, we focused on the analyses of tight junctions and ERM proteins to clarify the nature of the. epithelium. Major results are as follows:
1. Claudin-1-deficient mice were generated. Their epidermal barrier was affected, and the proliferation of epidermal cells appeared to be abnormal.
2. Claudin-5-deficient mice were generated. Their blood-brain barrier was affected in a size-dependent manner. This finding was intriguing from the viewpoint of drug deliver to the brain tumors.
3. The dynamic behavior of claudin-based tight junction strands was successfully observed in live cells. Their behavior was more dynamic than ever expected.
4. Snail, a transcription factor, plays a key role in the epithelial-mesenchymal transition, which is important in the metastasis of cancer cells. We found that Snail completely repressed the transcription of occludin and claudins through its direct binding to the E-boxes of the promoter regions of these genes.
5. Claudin-1 was shown to be overexpressed in human colon cancer (in collaboration with Prof. Nakamura's group).
6. We established the system, in which a certain gene can be double-knocked out in cultured epithelial cells. With this system, an epithelial cell line lacking the expression of ZO-1 and ZO-2 was established.
7. The structure of the gene product of NF2, an ERM-like tumor suppressor gene, was clarified by X-ray diffraction analyses (in collaboration with Prof.Hakozaki's group).

Report

(6 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • 2000 Annual Research Report
  • Research Products

    (42 results)

All 2005 2004 2003 2002 2001 Other

All Journal Article (18 results) Publications (24 results)

  • [Journal Article] Tight junctions in Schwann cells of peripheral myelinated axons : A lesson from claudin-19-deficient mice.2005

    • Author(s)
      Miyamoto, T. et al.
    • Journal Title

      J.Cell Biol. (in press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Achlorhydria by ezrin knockdown : defects in the formation/expansion of apical canaliculi in gastric parietal cells.2005

    • Author(s)
      Tamura, A.
    • Journal Title

      Journal of Cell Biology (印刷中)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] CLASP1 and CLASP2 bind to EB1 and regulate microtubule plus-end dynamics at the cell cortex.2005

    • Author(s)
      Mimori-Kiyosue, Y.
    • Journal Title

      Journal of Cell Biology 168・1

      Pages: 141-153

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Radixin deficiency causes deafness associated with progressive degeneration of cochlear stereocilia.2004

    • Author(s)
      Kitajiri, S.
    • Journal Title

      Journal of Cell Biology 166・4

      Pages: 559-570

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Establishment and characterization of cultured epithelial cells lacking expression of ZO-1.2004

    • Author(s)
      Umeda, K.
    • Journal Title

      Journal of Biological Chemistry 279・43

      Pages: 44785-44794

    • Related Report
      2004 Annual Research Report
  • [Journal Article] JACOP, a novel plaque protein localizing at the apical junctional complex with sequence similarity to cingulin.2004

    • Author(s)
      Ohnishi, H.
    • Journal Title

      Journal of Biological Chemistry 279・44

      Pages: 46014-46022

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Compartmentalization established by claudin-11-based tight junctions in stria vascularis is required for hearing.2004

    • Author(s)
      Kitajiri, S.
    • Journal Title

      Journal of Cell Science 117・21

      Pages: 5087-5096

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Dynamic behavior of paired claudin strands within apposing plasma membranes.2003

    • Author(s)
      Sasaki, H. et al.
    • Journal Title

      Proc.Natl.Acaci.Sci.USA 100

      Pages: 3971-3976

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Claudins in Caenorhabditis elegans : their distribution and barrier function in the epithelium.2003

    • Author(s)
      Asano, A. et al.
    • Journal Title

      Curr. Biol. 13

      Pages: 1042-1046

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Size-selective loosening of the blood-brain barrier in claudin-5-deficient mice.2003

    • Author(s)
      Nitta, T. et al.
    • Journal Title

      J.Cell Biol. 161

      Pages: 653-660

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Dynamic behavior of paired claudin strands within apposing plasma membranes.2003

    • Author(s)
      Sasaki, H. et al.
    • Journal Title

      Proc.Natl.Acad.Sci.USA 100

      Pages: 3971-3976

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Claudins in Caenorhabditis elegans : their distribution and barrier function in the epithelium..2003

    • Author(s)
      Asano, A. et al.
    • Journal Title

      Curr. Biol. 13

      Pages: 1042-1046

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Size-selective loosening of the blood-brain barrier in claudin-5-deficient mice.2003

    • Author(s)
      Nitta, T. et al.
    • Journal Title

      J. Cell Biol. 161

      Pages: 653-660

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Claudin-based tight junctions are crucial for the mammalian epidermal barrier : A lesson from claudin-1-deficient mice.2002

    • Author(s)
      Furuse, M. et al.
    • Journal Title

      J.Cell Biol. 156

      Pages: 1099-1111

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Claudin-based tight junctions are crucial for the mammalian epidermal barrier : A lesson from claudin-1-deficient mice.2002

    • Author(s)
      Furuse, M. et al.
    • Journal Title

      J. Cell Biol. 156

      Pages: 1099-1111

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Junctional adhesion molecule (JAM) binds to PAR-3 : a possible mechanism for the recruitment of PAR-3 to tight junctions.2001

    • Author(s)
      Itoh, M. et al.
    • Journal Title

      J.Cell Biol. 154

      Pages: 491-497

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Junctional adhesion molecule (JAM) binds to PAR-3 : a possible mechanism for the recruitment of PAR-3 to tight junctions.2001

    • Author(s)
      Itoh, M. et al.
    • Journal Title

      J. Cell Biol. 154

      Pages: 491-497

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Tight junctions in Schwann cells of peripheral myelinated axons : A lesson from claudin-19-deficient mice.

    • Author(s)
      Miyamoto, T. et al.
    • Journal Title

      J. Cell Biol. (In press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Publications] Sakaki, H. et al.: "Dynamic behavior of paired claudin strands within apposing plasma membranes"Pro.Natl.Acad.Sci.USA. 100. 3971-3976 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Nitta, T. et al.: "Size-selective loosening of the blood-brain barrier in claudin-5-deficient mice"J.Cell Biol.. 161. 653-660 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Asano, A. et al.: "Claudins in Caenorhabditis elegans : their distribution and barrier function in the epithelium"Curr.Biol.. 13. 1042-1046 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ikenouchi, J. et al.: "Regulation of tight junctions during epithelial-mesenchymal transition: Direct repression of the gene expression of claudins by Snail"J.Cell Sci.. 116. 1959-1967 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kubo, A. et al.: "Non-membranous granular organelle consisting of PCM-1: Subcellular distribution and cell cycle-dependent assembly/disassembly"J.Cell Sci.. 116. 919-928 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Matsuda, M. et al.: "A peculiar internalization of claudins, tight junction-specific adhesion molecules, during the intercellular movement of epithelial cells"J.Cell Sci.. 印刷中. (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Sasaki, H.: "Oynamic behavior of paired clandin strands within apposing plasma membranes"Proc. Natl. Acad. Sci. USA. (印刷中).

    • Related Report
      2002 Annual Research Report
  • [Publications] Kubo, A.: "Non-membranous granular organelle consisting of PCM-1 : Subcellular distribution and cell cycle-dependent assembly/disassembly"J. Cell Sci.. (印刷中).

    • Related Report
      2002 Annual Research Report
  • [Publications] Ikenouchi, J.: "Regulation of tight junctions during epithelial-mesenchymal transition : Direct repression of the gene expression of claudins/occludin by snail"J. Cell Sci.. (印刷中).

    • Related Report
      2002 Annual Research Report
  • [Publications] Kikuchi, S.: "Radixin deficioncy causes conjugated hyperbilirubinemia with loss of Mrp2 from bile canaliculor membranes"Nature Genetics. 31. 320-325 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hamazaki, Y.: "Multi-PDZ-domain-containing protein 1 (MUPP1) is concentrated at tight junctions through its possible interaction with claudins"J. Biol. Chem.. 277. 455-461 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Furase, M.: "Claudin-based tight junctions are crucial for the mammalian epiodermal barrier : A lesson from claudin-1-deficient mice"J. Cell Biol.. 156. 1098-1111 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Furuse, M.: "Claudin-based tight junctions are crucial for the mammalian epidermal barrier : A lesson from claudin-deficient mice"Journal of Cell Biology. (印刷中). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hamazaki, Y.: "Multi-PDZ-containing protein 1 (MUPP1) is concentrated at tight junctions through its possible interaction with claudin-1 and JAM"Journal of Biologyical Chemistry. 277. 455-461 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Itoh, M: "Junctional adhesion molecular (JAM) binds to PAR-3 : a possible mechanism for the recruitment of PAR-3 to tight junctions"Journal of Cell Biology. 154. 491-497 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Mimori-Kiyose, Y.: "Where is APC going?"Journal of Cell Biology. 154. 1105-1109 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Furuse, M.: "Conversion of Zonula Occludentes from tight to leaky stand type by introducing claudin-2 into MPCR I cells"Journal of Cell Biology. 153. 263-272 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Tsukita, S.: "Multi-functional strands in tight junctions"Nature Review of Molecular Cell Biology. 2. 285-293 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 月田承一郎: "Pores tin the wall : Claudins constitute tight junction strands containing aqueous pores"Journal of Cell Biology. 149. 13-16 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 三森,清末,優子: "Adenomatous polyposis coli (APC) protein moves along microtubules and concentrates at their growing ends in epithelial cells"Journal of Cell Biology. 148. 505-518 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 三森,清末,優子: "The dynamic behavior of EB1, an Adenomatous Poliposis Coli (APC) binding protein, on the distal ends of microtubules"Current Biology. 10. 865-868 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 斎藤通紀: "Complex phenotype of mice lacking occludin, a component of tight junction strands"Malecular Biology of the Cell. 11. 4131-4142 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 古瀬幹夫: "Conversion of Zonula Occludentes from tight to leaky strand type by introducing claudin-2 into MDCK I cells"Journal of Cell Biology. (印刷中). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] 月田承一郎: "Multifunctional strands in tight juncntions"Nature Review Molecular Cell Biology. (印刷中).

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2018-03-28  

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