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Analysis of cellular function of Neurofibromatosis Type 2 tumor suppressor gene product (Merlin)

Research Project

Project/Area Number 10671308
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Cerebral neurosurgery
Research InstitutionKumamoto University School of Medicine

Principal Investigator

ARAKI Norie  Kumamoto University School of Medicine, Tumor Genetics & Biology, Assistant Professor, 医学部, 助手 (80253722)

Co-Investigator(Kenkyū-buntansha) SAYA Hideyuki  Kumamoto University School of Medicine, Tumor Genetics & Biology, Professor, 医学部, 教授 (80264282)
Project Period (FY) 1998 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 1999: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 1998: ¥2,400,000 (Direct Cost: ¥2,400,000)
KeywordsNeurofibromatosis Type 2 / NF2 / Merlin / Tumor suppressor gene / Poly (ADP-ribose) polymerase (PARP) / Ku-antigen / Cellular signal transduction / Nuclear export signal (NES) / NF2、 / 神経繊維腫症2型
Research Abstract

The neurofibromatosis type 2 (NF2) is an autosomal dominantly inherited disorder, and strongly associated with development of benign intracranial tumors including bilateral vestibular schwannomas and meningiomas. NF2 gene was recently cloned, and the protein it encodes (termed as merlin/schwannomin) was found to be striking similarity to the moesin-ezrin-radixin (MER) family of cytoskeleton-associated proteins. To elucidate the biological function of NF2 protein (merlin), we analyzed the mutation pattern of merlin, its cellular localization, and the cellular signals via merlin. 1) NF2 gene mutations in NF2 patients were analyzed by protein truncation test. The majority of NF2 mutations are nonsense, frame shift, or exon-missing mutations. More than 70%of the mutations are clustered in the region encoding the N-terminal half of merlin. In addition, post-transrational proteolytic cleavage of N-terminal merlin by the ubiquitous protease calpain was found in some schwannomas and meningioma … More s. These results suggest that the N-terminal region of merlin is the most important for the tumor suppressive function, 2) Cellular expression systems of mutants or wild NF2 were established, and their cellular localization was analyzed by confocal lazer scanning Microscopy (CLSM). The wild merlin showed cytoplasmic and submembranous localization that was found to be directed by its nuclear export signal (NES) dependent transport mechanism. The N-terminal mutation resulted in nuclear accumulation of merlin. 3) Cellular binding proteins of merlin were purified from bovine brain extracts and identified as poly ADP-ribose polymerase, DNA-PK subunits Ku-antigen 85 and 70 by the analysis of their internal amino-acid sequences. The N-terminal(19-339) region of merlin is essential for their interaction. The immuno-precipitation, western blotting, and CLMS study confirmed their cellular co-localization. NF2 mutations impair the merlin-related complex formation and their cellular signal transport. This loss of cellular function of merlin may link to the intracranial tumor generation. Less

Report

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

    (27 results)

All Other

All Publications (27 results)

  • [Publications] masuko N, et al.: "Interaction of NE-dlg/SAP102, a neuron and endocrine tissue-specific membrane-associated guanylate kinase protein, with calmodulin and PSD-95/SAP90. A possible reguulatory role in molecular clustering at synaptic sites"J. Biol. Chem.. 274(9). 5782-5790 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Araki, N., Saya, H.: "Cellular signal transduction via the neurofibromatosis type 2 tumor supressor gene product; Merlin"Seikagaku. 71(2). 43-49 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Shibayama R. et al.: "Autoantibody against N(epsilon)-(carboxymethyl)lysine: an advanced glycation end product of the Maillard reaction"Diabetes.. 48(9). 1842-1849 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Kuwahara H. et al.: "A novel NE-dlg/SAP102-associated protein, p51-nedasm, related to the aminohydrolyse superfamily, interferes with the association between NE-dlg/SAP102 and NMDA receptor"J. Biol. Chem.. 274(45). 32204-322014 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Ito K. et al.: "Calcium influx triggers the sequential protelysis of extracellular and cytoplasmic domains of E-cagherin. Leading to loss of b-catenin from cell-cell contcts"Oncogene. 18(50). 7080-7090 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 荒木令江、et.al.: "NF2遺伝子の変異特性とNF2蛋白マーリンの機能解析"日本皮膚科学会雑誌. 109(12). 1938-1941 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 荒木令江、et.al.: "NF2遺伝子の機能"遺伝性癌の分子医学""現代医療. 31(9). 2315-2321 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Kimura,Y. Koga,H. Araki,N. Mugita,N. Fujita,N. Takashima,H. Nishi,T. Yamashima,T. Saido,T.C. Yamasaki,T. Moritake,K. Saya,H. and Nakao,M: "The involvement of calpain-dependent proteolysis of the tumor suppressor NF2 (merlin) in schwannomas and meningiomas"Nature Medicine. 4. 915-922 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Koga,H. Araki,N. Hirota,T. Kumura,Y. Nakao,M. and Saya,H: "Impairment of cell adhesion by expression of the mutant neurofibromatosis type 2 (NF2) gene products missing exon in ERM-homology domain"Oncogene. 17. 801-810 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Masuko N, Makino K, Kuwahara H, Fukunaga K, Sudo T, Araki N, Yamamoto H, Yamada Y, Miyamoto E, and Saya H: "Interaction of NE-dlg/SAP102, a neuronal and endocrine tissue-specific membrane-associated guanylate kinase protein, with calmodulin and PSD-95/SAP90. A possible regulatory role in molecular clustering at synaptic sites"J. Biol. Chem. 274. 5782-5790 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Araki N, and Saya H: "Cellular signal transduction via the neurofibromatosis type 2 tumor supressor gene product; Merlin"Seikagaku. 71. 43-49 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Shibayama R, Araki N, Nagai R, and Horiuchi S: "Autoantibody against N(epsilon)-(carboxymethyl)lysine: an advanced glycation end product of the Maillard reaction"Diabetes. 48. 1842-1849 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Ito K, Okamoto I, Araki N, Kawano Y, Nakao M, Fujiyama S, Tomita K, Momori T, and Saya H: "Calcium influx triggers the sequential proteolysis of extracellular and cytoplasmic domains of E-cadherin, Leading to loss of b-catenin from cell-cell contacts"Oncogene. 18. 7080-7090 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Kuwahara H, Araki N, Makino K, Masuko N, Honda S, Kaibuchi K, Fukunaga K Miyamoto E, Ogawa M, and Saya H: "A novel NE-dlg/SAP102-associated protein, p51-nedasin, related to the aminohydrolyse superfamily, interferes with the association between NE-dlg/SAP102 and NMDA receptor"J. Biol. Chem.. 274. 32204-32214 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Araki N., Morimasa T., Sakai T., Kamo M., Tokuoh H., Yunoue S., Miyazaki., Abe K., Saya H., Tsugita A.: "Comparative analysis of brain proteins from p53 deficient mice by two-dimensional electrophoresis"Electrophoresis. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Masuko N,et.al.: "Interaction of NE-dlg/SAP102,a neuronal and endocrine tissue-specific membrane-associated guanylate kinase protein,with calmodulin and PSD-95/SAP90.A possible regulatory role in molecular clustering at synaptic sites."J.Biol.Chem.. 274(9). 5782-5790 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Araki,N.,Saya,H.: "Cellular signal transduction via the neurofibromatosis type 2 tumor supressor gene product;Merlin."Seikagaku. 71(2). 43-49 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Shibayama R.et.al.: "Autoantibobody against N(epsilon)-(carboxymethyl)lysine:an advanced glycation end product of the Maillard reaction."Diabetes.. 48(9). 1842-1849 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kuwahara H,et.al.: "A novel Ne-dlg/SAP102-associated protein,p51-nedasin,related to the aminohydrolyse supertamily,interferes with the association between NE-dig/SAP102 and NMDA receptor."J.Biol.Chem.. 274(45). 32204-32214 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Ito K et.al: "Calcium influx triggers the sequential proteolysis of extracellular and cytoplasmic domains of E-cadherin,Leading to loss of b-catenin front cell-cell contacts."Oncogene.. 18(50). 7080-7090 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 荒木令江、et.al.: "NF2遺伝子の変異特性とNF2蛋白マーリンの機能解析"日本皮膚科学会雑誌. 109(12). 1938-1941 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 荒木令江、et.al.: "NF2遺伝子の機能"遺伝子性癌の分子医学""現代医療. 31(9). 2315-2321 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Araki,N.et.al.: "Comparative analysis of brain proteins from p53 deficient mice by two-dimensional electrophoresis."Electrophoresis.. (in press).

    • Related Report
      1999 Annual Research Report
  • [Publications] Koga,H. et.al.: "Impairment of cell adhesion by expression of the mutat neurofibromatosis type 2(NF2) gene products missing exon in ERM-homology domain." Oncogene. 17. 801-810 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kimura,Y. et.al.: "The involvement of caipain-dependent proteolysis of the tumor suppressor NF2(merlin) in schwannomas and meningiomas." Nature Medicine. 4(8). 915-922 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Masuko,N. et.al.: "Interaction of NE-dlg/SAP102,a neuronal and endocrine tissue-specific membrane-associated guanylate kinase protein,with calmodulin and PSD-95/SAP90,A possible regulatory rolo in molecular clustering at synaptic sites." J.Biol.Chem.274(9). 5782-5790 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Araki,N.: "Cellular signal transduction via the neurofibromatosis type 2 tumor supressor gene product;Merlin." Seikagaku. 71(2). 43-49 (1999)

    • Related Report
      1998 Annual Research Report

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

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