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Intracellular signaling and endocytosis of the growth factor midkine

Research Project

Project/Area Number 14580647
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Functional biochemistry
Research InstitutionNagoya University

Principal Investigator

KADOMATSU Kenji  Nagoya University, Graduate School of Medicine, Associate Professor, 大学院・医学系研究科, 助教授 (80204519)

Co-Investigator(Kenkyū-buntansha) MURAMATSU Hisako  Nagoya University, Graduate School of Medicine, Associate Professor, 大学院・医学系研究科, 助教授 (50182134)
Project Period (FY) 2002 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2003: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2002: ¥1,900,000 (Direct Cost: ¥1,900,000)
Keywordsmidkine / LRP / Nucleolin / nuclear targeting / growth factor / LDL receptor / proteasome / lysosome / nucleolin / PTPS / アポトーシス
Research Abstract

This study has been aimed to elucidate the role(s) of endocytosed midkine (MK), a heparin-binding growth factor. MK is implicated in cancer development, neural survival, and inflammation. One of its receptors is LDL receptor-related protein (LRP), a member of the LDL receptor family. We demonstrated in this study that LRP is responsible for MK endocytosis, endocytosed MK binds to the nucleo-cytoplasmic shuffle protein nucleolin, and the nucleolin-bound MK enters the nucleus. This nuclear targeting by MK is needed for MK-mediated cell survival. We further clarified that the nuclear targeting MK is degraded by the proteasome system. Thus, proteasome inhibitors promote MK stability in the nucleus, and cytoplasmically expressed MK is polyubiquitinated. The N-terminal half domain of MK is important for proteasome-mediated degradation, while the C-terminal half domain is sufficient for nuclear localization. In summary, this study has revealed an important biological function of endocytosed nuclear targeting MK, i.e. anti-apoptosis, and a degradation mechanism of an endocytosed growth factor. We also report some important findings as to MK and cancer, including validity as a tumor marker as well as a molecular target for cancer therapy.

Report

(3 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • Research Products

    (24 results)

All Other

All Publications (24 results)

  • [Publications] N Suzuki et al.: "Proteasomal degradation of the nuclear targeting growth factor midkine."J.Biol.Chem.. (In press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] S Ikematsu et al.: "Correlation of elebated level of blood midkine with poor prognostic factors of hyman neuroblastomas."Br.J.Cancer. 88. 1522-1526 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] M Tomizawa et al.: "A promoter region of the midkine gene that is frequently expressed in human hepatocelluar carcinoma can activate a suicide gene as effectively as the alpha-fetoprotein promoter."Br.J.Cancer. 89. 1086-1090 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] S Ikematsu et al.: "High levels of urinary midkine in various cancer patients."Biochem.Biophys.Res.Commun.. 306. 329-332 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Y Shibata et al.: "Nuclear targeting by the growth factor midkine."Mol.Cell.Biol.. 22. 6788-6796 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Y Takei et al.: "5'-,3'-inverted thymidine-modified antisense oligodeoxynucleotide targeting midkine. Its design and application for cancer therapy., -"J.Biol.Chem.. 277. 23800-23806 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Suzuki, N., Shibata, Y, Urano, T., Murohara, T., Muramatsu, T., Kadomatsu K.: "Proteasomal degradation of the nuclear targeting growth factor midkine."J.Biol.Chem.. (In press.).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Ikematsu, S., Nakagawara, A., Nakamura, Y., Sakama, S., Wakai, K., Muramatsu, T., Kadomatsu, K.: "Correlation of elevated level of blood midkine with poor prognostic factors of human neuroblastomas."Br.J.Cancer. 88. 1522-1526 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Tomizawa, M., Yu, L., Wada, A., Tamaoki, T., Kadomatsu, K., Muramatsu, T., Matsubara, S., Watanabe, K., Ebara, M., Saisho, H., Sakiyama, S., Tagawa, M.: "A promoter region of the midkine gene that is frequently expressed in human hepatocellular carcinoma can activate a suicide gene as effectively as the alpha-fetoprotein promoter."Br.J.Cancer. 89. 1086-1090 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Ikematsu, S., Okamoto, K., Yoshida, Y., Oda, M., Sugano-Nagano, H., Ashida, K., Kumai, H., Kadomatsu, K., Muramatsu, H., Muramatsu, T., Sakuma S.: "High levels of urinary midkine in various cancer patients."Biochem.Biophys.Res.Commun.. 306. 329-332 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shibata, Y, Muramatsu, T., Hirai, M., Inui, T., Kimura, T., Saito, H., Lynn M.McCormick, L.M., Bu, G., Kadomatsu, K.: "Nuclear targeting by the growth factor midkine."Mol.Cell.Biol.. 22. 6788-6796 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Takei, Y., Kadomatsu, K., Itoh, H., Sato, W., Nakazawa, K., Kubota, S., Muramatsu, T.: "5'-,3'-inverted thymidine-modified antisense oligodeoxynucleotide targeting midkine. Its design and application for cancer therapy."J.Biol.Chem.. 277. 23800-23806 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] N Suzuki et al.: "Proteasomal degradation of the nuclear targeting growth factor midkine"J.Biol.Chem.. (In press).

    • Related Report
      2003 Annual Research Report
  • [Publications] S Ikematsu et al.: "Correlation of elevated level of blood midkine with poor prognostic factors of human neuroblastomas"Br.J.Cancer. 88. 1522-1526 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] H Shimada et al.: "Increased serum midkine concentration as a possible tumor marker in patients with superficial esophageal cancer"Oncol.Rep.. 10. 411-414 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] S Ikematsu et al.: "High levels of urinary midkine in various cancer patients"Biochem.Biophys.Res.Common.. 306. 329-332 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] M Tomizawa et al.: "A promoter region of the midkine gene that is frequently expressed in human hepatocellular carcinoma can activate a suicide gene as effectively as the alpha-fetoprotein promoter"Br.J.Cancer. 89. 1086-1090 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] L Yu et al.: "Cell growth- and P53-dependent transcriptional activity of the midkine promoter confers suicide gene expression in tumor cells"Oncol.Rep.. 10. 1301-1305 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Shibata et al.: "Nuclear targeting by the growth factor midkine"Mol. Cell. Biol.. 22. 6788-6796 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Takei et al.: "5'-, 3'-inverted thymidine-modified antisense oligodeoxynucleotide targering midkine. Its design and application for cancer therapy"J. Biol. Chem.. 277. 23800-23806 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Uchimura et al.: "Functional analysis of the chondroitin 6-sulfotransferase gene in relation to lymphocyte subnonulations brain development and oversulfated chondroitin sulfates"J. Biol. Chem.. 277. 1443-1450 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yanada et al.: "Impact of antithrombin deficiency in thrombogenesis : lipopolysaccharide and stress-induced thrombus formation in heterozygous antithrombin dificient mice"Blood. 99. 2455-2458 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Matsuura: "Midkine expression is associated with postnatal development of the lungs"Cell Strixct. Funct.. 27. 109-115 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yoshida et al.: "A promoter region of midkine gene can activate transcription of an exogenous suicide gene in human nancreatic cancer"Anticancer Res.. 22. 117-120 (2002)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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