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2000 Fiscal Year Final Research Report Summary

Role of NF2 tumor suppressor gene promoter in the tumorigenesis

Research Project

Project/Area Number 11671371
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Cerebral neurosurgery
Research InstitutionKagoshima University (2000)
Kumamoto University (1999)

Principal Investigator

TAKESHIMA Hideo  University Hospital Faculty of Medicine, Kagoshima university, Assistant Professor, 医学部・附属病院, 講師 (70244134)

Co-Investigator(Kenkyū-buntansha) KURATSU Jun-ichi  Faculty of Medicine, Kagoshima university, Professor, 医学部, 教授 (20145296)
USHIO Yukitaka  Faculty of Medicine, Kumamoto University, Professor, 医学部, 教授 (20028583)
NISHI Toru  University Hospital Faculty of Medicine, Kumamoto University, Research Associate, 医学部・附属病院, 助手 (00264309)
Project Period (FY) 1999 – 2000
KeywordsNF2 / gene / promoter / cloning / luciferase / methylation
Research Abstract

Background : Although mutational inactivation and allelic loss in the NF2 gene appear to be causal events in the majority of vestibular schwannomas, involvement of another potentially important mechanism, transcriptional inactivation, has not been investigated. Results : We cloned and functionally characterized the 5'-flanking region of the human NF2 gene and identified the molecular mechanisms that regulate NF2 expression. Luciferase assay and site-directed mutagenesis demonstrated that a 70-base pair (bp) region (-591 to -522 bp from the translation start site) was essential for the basic expression of the NF2 gene. Gel mobility shift assay indicated recognition by nuclear protein(s) of the unusually long (〜66 bp) sequences in this region. Recognition was inhibited by either mutation of the binding core sequence or by methylation of three CpG sites. Point mutations at these CpG sites significantly decreased promoter activity, suggesting the importance of these sites. In 14 of 23 vestibular schwannomas, these 3 CpG sites within this region were methylated in a site-specific manner and the methylation status was consistent with the expression of NF2 mRNA.Conclusions : Suppressed expression by aberrant methylation or mutation of the promoter elements could be an alternative mechanism for inactivation of the NF2 gene.

  • Research Products

    (12 results)

All Other

All Publications (12 results)

  • [Publications] Yamamoto K, et al: "Cloning and functional characterization of the 5'-flanking region of the human monocyte chemoattractant protein-1 promoter (CCR2) gene."J Biol Chem. 274. 4646-4654 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Takeshima H, et al: "Identification and characterization of the cis-regulatory element in NF2 gene promoter that is inactivated by methylation in vestibular schwannomas."Neuro-Oncology. 1. S76 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Goto T, et al.: "High efficient electro-gene therapy of solid tumor by using an expression plasmid for the herpes simplex virus thymidine kinase gene."Proc Natl Acad Sci USA. 97. 354-359 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Takeshima H, et al.: "Application of advances in molecular biology to the treatment of brain tumors."Current Oncology Reports. 2. 425-433 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kino T, et al.: "Identification of the cis-acting region in the NF2 gene promoter as a potential target for mutation and methylation-dependent silencing in schwannoma."Genes to Cells. 6. 1-15 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Koga H, et al.: "Biological aspects of the neurofibromatosis type 2 gene product.In Phacomatosis in Japan"H.Nimura,F.Otsuka and O.Hino. 11 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yamamoto, K., Takeshima, H., Hamada, K., Nakao, M., Kino, T., Nishi, T., Kochi, M., Kuratsu, J., Yoshimura, T., and Ushio, Y.: "Cloning and functiional characterization of the 5'-flanking region of the human monocyte chemoattractant protein-1 receptor (CCR2) gene.-Essential role of 5'-untranslated region in tissue specific expression."J.Biol.Chem.. 274. 4646-4654 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Takeshima, H., Kino, T., Nishi, T., Yamamoto, K., Kimura, T., Saito, T., Kochi, M., and Ushio, Y.: "Identification and characterization of the cis-regulatory element in NF2 gene promoter that is inactivated by methylation in vestivular schwannomas."Neuro-Oncology. 1. S76 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Goto T, Nishi T, Tamura T, Dev SB, Takeshima H, Kochi M, Yoshizato K, Kuratsu J, Sakata T, Hofmann GA and Ushio Y.: "High efficient electro-gene therapy of solid tumor by using and expression plasmid for the herpes simplex virus thymidine kinase gene."Proc.Natl.Acad.Sci.USA. 97. 354-359 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Takeshima, H., Sawamura, Y., Gilbert, M.R., Van Meir, E.G.: "Application of advances in molecular biology to the treatment of brain tumors."Current Oncology Reports. 2. 425-433 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kino, T., Takeshima, H., Nishi, T., Yamamoto, K., Nakao, M., Saito, Y., Kochi, M., Kuratsu, J., Saya, H., and Ushio, Y.: "Identification of the cis-acting region in the NF2 gene promoter as a potential target formutation and methylation-dependent silencing in schwannoma."Genes to Cells. 6. 1-15 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Koga, H., Takeshima, H., Araki, N.and Saya, H.: "Biological aspects of the neurofibromatosis type 2 gene product."Phacomatosis in Japan.H.Nimura, F.Otsuka, and O.Hiho (Ed.) Japan Scientific Societies Press (Karger), Tokyo. 153-163 (1999)

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

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Published: 2002-03-26  

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