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2005 Fiscal Year Final Research Report Summary

Studies on molecular target thrapeutics that sensitize cancer cells to anoikis

Research Project

Project/Area Number 16590077
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Biological pharmacy
Research InstitutionNational Institute of Infectious Diseases

Principal Investigator

FUKAZAWA Hidesuke  National Institute of Infectious Diseases, Department of Bioactive Molecules, Chief, 生物活性物質部, 室長 (10218878)

Project Period (FY) 2004 – 2005
Keywordsanchorage-independent growth / anoiks / apoptosis / BH3-only proteins / Bim / ERK / MEK inhibitors
Research Abstract

Loss of contact with substratum triggers apoptosis in many normal cell types, a phenomenon termed anoikis. We found that mitogen-activated protein /extracellular signal-regulated kinase kinase (MEK) inhibitors induced apoptosis in two human breast cancer cells when nonanchored, while anchored cells remained viable. To analyze the biochemistry behind this event, we measured the amounts of Bcl-2 family proteins. Upon treatment with MEK inhibitors, BimEL in these cells rapidly increased, irrespective of the state of anchorage. However, it translocated to mitochondria only in nonanchored cells, explaining why attached cells remain viable. The two sensitized cell lines had exceedingly low basal levels of BimEL compared to other breast cancer cell lines, suggesting that maintenance of low BimEL amount, is important for survival of these cell lines. MEK inhibitors also induced the electrophoretic mobility shift of BimEL, indicative of reduced phosphorylation. In vitro, BimEL was phosphorylated by extracellular signal-regulated kinase (ERK) on serine 69, which resides in the BimEL-specific insert region. Using phosphospecific antibody against this site, we showed that this residue is actually phosphorylated in cells. We also showed that phosphorylation of senile 69 promotes ubiquitination of BimEL. We conclude that MEK inhibitors sensitize certain cancer cells to anoikis by blocking phosphorylation and hence degradation of BimEL, a mechanism which these cells depend on to escape anoikis. Our results also imply a role for BimEL as a biochemical marker for prognosis and diagnosis of efficacy of MEK inhibitors.

  • Research Products

    (12 results)

All 2005 2004 Other

All Journal Article (12 results)

  • [Journal Article] Reduction of Hepatitis C virus NS5A phosphorylation through its interaction with amphiphysin II.2005

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

      Biochem. Biophys. Res. Commun. 336

      Pages: 572-578

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Reduction of Hepatitis C virus NS5A phosphorylation through its interaction with amphiphysin II.2005

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

      Biochem.Biophys.Res.Commun. 336

      Pages: 572-578

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] BifflEL is an important determinant for induction of anoikis sensitivity by mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitors.2004

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

      Mol. Cancer Ther. 3

      Pages: 1281-1288

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Nucleolar Nekll is a novel target of Nek2A in G1/S-arrested cells.2004

    • Author(s)
      Noguchi, K., et al.
    • Journal Title

      J. Biol. Chem. 279

      Pages: 32716-32727

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Poly (ADP-ribose) polymerase-1 inhibits ATM kinase activity in DNA damage response.2004

    • Author(s)
      Watanabe F., et al.
    • Journal Title

      Biochera. Biophys. Res. Commun. 319

      Pages: 596-602

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] BimEL is an important determinant for induction of anoikis sensitivity by mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitors.2004

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

      Mol.Cancer Ther. 3

      Pages: 1281-1288

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Nucleolar Nekil is a novel target of Nek2A in G1/S-arrested cells.2004

    • Author(s)
      Noguchi, K., et al.
    • Journal Title

      J.Biol.Chem. 279

      Pages: 32716-32727

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Regulation of SV40 large T antigen acetylation by multiple histone deacetylases and binding proteins.

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

      Oncogene (In press)

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Nucleolin is involved in InteΥΥeron Regul atory Factor-2 dependent transcriptional activation.

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

      Oncogene (In press)

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Regulation of SV40 large T antigen acetylation by multiple histone deacetylases and binding proteins.

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

      Oncogene (in press)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Nucleolin is involved in Interferon Regulatory Factor-2 dependent transcriptional activation.

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

      Oncogene (in press)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Poly (ADP-ribose) polymerase-1 inhibits ATM kinase activity in DNA damage response.

    • Author(s)
      Watanabe F., et al.
    • Journal Title

      Biochem.Biophys.Res.Commun. 319

      Pages: 596-602

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2007-12-13  

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