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Functional Analysis of the von Hippel-Lindau Disease Tumor Suppressor Gene

Research Project

Project/Area Number 10671488
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Urology
Research InstitutionYokohama City University

Principal Investigator

YAO Masahiro  School of Medicine, Urology, Yokohama City University, Assistant Professor, 医学部, 講師 (00260787)

Co-Investigator(Kenkyū-buntansha) KISHIDA Takeshi  School of Medicine, Urology, Yokohama City University, Faculty Staff, 医学部, 助手 (60254166)
穂坂 正彦  横浜市立大学, 医学部, 教授 (30106330)
Project Period (FY) 1998 – 1999
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 1999: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 1998: ¥1,700,000 (Direct Cost: ¥1,700,000)
KeywordsVHL gene / tumor suppressor gene / renal cell carcinoma / 腎細胞癌 / DHL遺伝子
Research Abstract

We found that, in normal human renal proximal tubule epithelial cells, the steady-state amount of VHL protein is strictly regulated by cell density. The cellular VHL content is more than 100-fold higher in dense cultures than in sparse cultures. The growth rates of renal cell cacinoma cells lacking an intact VHL gene and their derivatives with wild-type or mutant VHL expression vector do not differ significantly when they are growing in log-phase. Importantly, however, there is a difference when they reach confluency : cells lacking wild-type VHL grew continuously, while cells expressing exogenous VHL protein showed relatively limited cell growth. VHL protein functions as a growth suppressor at high cell density, and this might be the basis of the tumor suppressor function of VHL. We investigated the role of the VHL gene in CNS development using rodent CNS progenitor cells. We show that expression of the VHL protein is correlated with neuronal differentiation but not with glial differe … More ntiation in CNS progenitor cells, and we also show that VHL gene transduction induces neuronal differentiation. In addition, a VHL mRNA antisense oligonucleotide inhibits differentiation of CNS progenitor cells and up-regulates their cell cycle. The VHL protein contains two domains, alpha and beta. We report that the beta-domain interacts directly with atypical PKC isotypes, PKC zeta and PKC lambda. Further, the regulatory domain of aPKC is sufficient for this direct protein-protein interaction. To investigate the potential role of the PTEN gene in renal tumorigenesis, we searched for abnormalities of the gene in 68 primary renal-cell carcinomas (RCCs) as well as in 17 renal carcinoma-derived cell lines. Five of 68 (7.5 %) primary RCCs exhibited intragenic mutations, and 1 of 17 (5.9 %) cell lines had an insertion mutation. Four of the 5 primary tumors with PTEN mutation were high-grade, advanced clear-cell RCCs with distant metastases or renal vein tumor invasions, resulting in poor prognostic courses. PTEN mutation is observed m a subset of RCCs and that, especially in clear-cell RCCs, it occurs as a late-stage event and may contribute to the invasive and/or metastatic tumor phenotype. Less

Report

(3 results)
  • 2001 Final Research Report Summary
  • 1999 Annual Research Report
  • 1998 Annual Research Report
  • Research Products

    (13 results)

All Other

All Publications (13 results)

  • [Publications] Yao M, Kondo K et al.: "Molecular genetics of the kidney cancers ; Implication of the VHL tumor suppressor gene"Monograph on Cancer Research. 46. 205-214 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Okuda H, Yao M et al.: "Direct interaction of the β-domain of the VHL tumor suppressor protein with the regulatorv domain of atypical PKC isotypes"Biochem Biophys Res Commun. 263・2. 491-497 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yoshida M, Yao M et al.: "Germ-line Mutation Analysis in Patients with Von Hippel-Lindau Disease in Japan : an Extended Study of 77 Families"Jpn J Cancer Res. 91・2. 201-212 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kanno H, Yao M et al.: "Role of the von Hippel-Lindau tumor suppressor protein during neuronal differentiation"Cancer Res. 60・11. 2820-2824 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kondo K, Yao M et al.: "PTEN/MMAC1/TEP1 mutations in human primary renal cell carcinomas and renal carcinoma cell lines"Int J Cancer. 91・2. 219-224 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Baba M, Yao M et al.: "Tumor suppressor protein VHL is induced at high cell density and mediates contact inhibition of cell growth"Oncogene. 20・22. 2727-2736 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yao M, Kondo K, Yoshida M, Kishida T, Shuin T: "Molecular genetics of the kidney cancers ; Implication of the VHL tumor suppressor gene"Monograph on Cancer Research, No.46, Japan Scientific Societies Press. 205-214 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Okuda H, Hirai S, Takaki Y, Kamata M, Baba M, Sakai N, Kishida T, Yao M, Ohno S, Shuin T: "Direct interaction of the β domain of the VHL tumor suppressor protein with the regulatory domain of atypical PKC isotypes"Biochem Biophys Res Commun. 263-2. 491-497 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yoshida M, Ashida S, Kondo K, Kobayashi K, Kanno H, Shinohara N, Shitara N, Kishida T, Kawakami S, Baba M, Yamamoto I, Hosaka M, Shuin T, Yao M: "Germ-line Mutation Analysis in Patients with Von Hippel-Lindau Disease in Japan : an Extended Study of 77 Families"Jpn J Cancer Res. 91-2. 204-212 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kanno H, Saljooque F, Yamamoto I, Hattori S, Yao M, Shuin T: "UH-S, Role of the von Hippel-Lindau tumor suppressor protein during neuronal differentiation"Cancer Res. 60-11. 2820-2824 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kondo K, Yao M, Kobayashi K, Yoshida M, Kaneko S, Baba M, Sakai N, Kishida T, Kawakami S, Nagashima Y, Nakatani Y, Hosaka M: "PTEN/MMAC1/TEP1 mutations in human primary renal cell carcinomas and renal carcinoma cell lines"Int J Cancer. 91-2. 219-224 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Baba M, Hirai S, Kawakami S, Kishida T, Sakai N, Kaneko S, Yao M, Shuin T, Kubota Y, Hosaka M, Ohno S: "Tumor suppressor protein VHL is induced at high cell density and mediates contact inhibition of cell growth"Oncogene. 20-22. 2727-2736 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Okuda H.et al.: "Direct interaction of the beta-domain of OHL funor suppare esor protein with the regulatory domain of atypical PKC isofypes."Biochem. Biophys. Res. Comman. 263. 491-497 (1999)

    • Related Report
      1999 Annual Research Report

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Published: 1998-04-01   Modified: 2016-04-21  

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