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New clearance system of abnormal protein in Polyglutammine disease

Research Project

Project/Area Number 13480258
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Neurochemistry/Neuropharmacology
Research InstitutionKyushu University

Principal Investigator

NAKAYAMA Keiichi  Kyushu University, Med. Inst. of Bioreg., Prof., 生体防御医学研究所, 教授 (80291508)

Co-Investigator(Kenkyū-buntansha) NAKAYAMA Keiko  Tohoku Univ. Faculty of Med., Prof., 大学院・医学系研究科, 教授 (60294972)
HATAKEYAMA Shigetsugu  Kyushu University, Med. Inst. of Bioreg., Ass. Prof., 生体防御医学研究所, 助教授 (70294973)
Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥15,100,000 (Direct Cost: ¥15,100,000)
Fiscal Year 2002: ¥5,200,000 (Direct Cost: ¥5,200,000)
Fiscal Year 2001: ¥9,900,000 (Direct Cost: ¥9,900,000)
KeywordsMJD / UFD2 / VPC / polyglutamine Disease / Ubiquitylation / MJD1 / ノックアウトマウス
Research Abstract

Machado-Joseph disease (MJD)/Spinocerebellar ataxia type 3 (SCA3) is neurodegenerative disease which is caused by polyglutamine expansion in a responsible gene product, MJD1/Ataxin3. MJD1 has now been shown to undergo ubiquitylation and degradation by proteasome-dependent pathway. MJD1 with expanded polygiutamine tract was more resistant to degradation than normal MJD1. We established an in vitro system of ubiquitylation of MJD1, thereby biochemically purified activity to mediate polyubiquitylation of MJD1 from rabbit reticulocyte lysate. An AAA-family ATPase VCP was isolated from the active fraction, and found to binds to MJD1. Furthermore, UFD2a, a mammalian ubiquitin-chain assembly factor (E4), associated with VCP and induced polyubiquitylation of MJD1. UFD2a markedly promoted ubiquitylation and degradation of MJD1 with expanded polyglutamine tract, resulting in the clearance of MJD1 protein. In contrast, dominant-negative mutant UFD2a reduced the degradation rate of MJD1, leading to the formation of intracellular aggregation. In Drosophila model, overexpression of UFD2a significantly suppressed the neurodegeneration induced by expression of MJD1 with expanded polyglutamine tract. These findings suggest that E4 is a ratelimiting factor of degradation of pathologic polyglutamine-containing proteins, and may give a potential tool for gene therapy to control the clinical conditions of MJD

Report

(3 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • Research Products

    (66 results)

All Other

All Publications (66 results)

  • [Publications] Minamishima, Y.A. et al.: "Recovery of liver mass without proliferation of hepatocytes after partial hepatectomy in Skp2-deficient mice"Cancer Res.. 62. 995-999 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yoshida, K. et al.: "Involvement of p27^<KIP1> degradation by Skp2 in the regulation of proliferation in response to wounding of corneal epithelium"Invest. Ophthalmol. Vis. Sci.. 43. 364-370 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Koguchi, K. et al.: "Modulation of astrocyte proliferation by cyclin-dependent kinase inhibitor p27Kip1"Glia. 37. 93-104 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ikebe, C. et al.: "Isolation and characterization of a novel F-Box protein Pof10 in fission yeast"Biochem. Biophys. Res. Commun.. 290. 1399-1407 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yamanaka, A. et al.: "Multiple Skp1-related proteins in Caenorhabditis elegans. Diverse patterns of interaction with Cullins and F-box proteins"Curr. Biol.. 12. 267-275 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kanematsu, T. et al.: "Role of the PLC-related, catalytically inactive protein p130 in GABA_A receptor function"EMBO J.. 21. 1004-1011 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Miyamoto A. et al.: "Increased proliferation of B cells and auto-immunity in mice lacking protein kinase Cδ"Nature. 416. 865-869 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Masuda T. et al.: "Clinical and biological significance of S-phase kinase-associated protein 2 (Skp2) gene expression in gastric carcinoma : modulation of malignant phenotype by Skp2 overexpression, possibly via p27"Cancer Res.. 62. 3819-3825 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Imai Y.et al.: "CHIP is associated with Parkin, a gene responsible for familial Parkinson's disease, and enhances its ubiquitin ligase activity"Mol. Cell. 10. 55-67 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Garcia-Fernandez. et al.: "Aplidin induces the mitochondrial apoptotic pathway via oxidative stress-mediated JNK and p38 activation and protein kinase Cδ"Oncogene. 21. 7533-7544 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nakamichi I. et al.: "Formation of Mallory body-like Inclusions and cell death induced by deregulated expression of keratin 18"Mol. Biol. Cell. 13. 3411-3451 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shimoda K. et al.: "Tyk2 is required for the induction and nuclear translocation of Daxx which regulates IFN-α-induced suppression of B lymphocyte formation"J. Immunol.I. 169. 4707-4711 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Seto Y.et al.: "Enhanced Th2 cell-mediated allergic inflammation in Tyk2-deficient mice"J. Immunol. 170. 1077-1083 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kaneko C. et al.: "Characterization of the mouse gene for the U-box-type ubiquitin ligase UFD2a"Biochem. Biophys. Res. Commun.. 300. 297-304 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tomari SI et al.: "Glomerular differentiation in p27 and p57 double-mutant metanephroi"Anat. Embryol.. 206. 31-36 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shirane M. et al.: "Inherent calcineurin inhibitor FKBP38 targets Bcl-2 to mitochondria and inhibits apoptosis"Nature Cell Biol.. 5. 28-63 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shimoda, K. et al.: "Partial impairment of interleukin-12 (IL-12) and IL-18 signaling in Tyk2-deficient mice"Blood. 99. 2094-2099 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ishida N. et al.: "Phosphorylation of p27^<Kip1> on serine 10 is required for its binding to CRM1 and nuclear export"J. Biol. Chem.. 277. 14355-14358 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hara, T. et al.: "Degradation of p27Kip1 at the G0-G1 transition mediated by a Skp2-independent ubiquitination pathway"J. Biol. Chem.. 276. 48937-48943 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Malek, N.P.et al.: "A mouse knock-in model exposes sequential proteolytic pathways that regulate p27Kip1 in G1 and S phase"Nature. 413. 323-327 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nagahama, H. et al.: "Spatial and temporal expression patterns of the cyclin-dependent kinase (CDK) inhibitors p27Kip1 and p57Kip2 during mouse development"Anat. Embryol.. 203. 77-87 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Minamishima Y. A. et. al.: "Recovery of liver mass without proliferation of hepatocytes after partial hepatectomy in Skp2- deficient mice"Cancer Res.. 62. 995-999 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yoshida K., et. al.: "Involvement of p27^<KIP1> degradation by Skp2 in the regulation of proliferation in response to wounding of corneal epithelium"Invest. Ophthalmol. Vis. Sci.. 43. 364-370 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Koguchi K., et. al.: "Modulation of astrocyte proliferation by cyclin-dependent kinase inhibitor p27^<KIP1>"Glia.. 37. 93-104 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ikebe C. et.al.: "Isolation and characterization of a novel F-Box protein Pof10 in fission yeast"Biochem. Biophys. Res. Commun.. 290. 1399-1407 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yamanaka A. et. al.: "Multiple Skp1-related proteins in Caenorhabditis elegans. Diverse patterns of interaction with Cullins and F-box proteins"Curr. Biol.. 12. 267-275 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kanematsu T. et. al.: "Role of the PLC-related, catalytically inactive protein p130 in GABA_A receptor function"EMBO J.. 21. 1004-1011 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Miyamoto A. et. al.: "Increased proliferation of B cells and auto- immunity in mice lacking protein kinase Cδ"Nature. 416. 865-869 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Masuda T. et. al.: "Clinical and biological significance of S-phase kinase-associated protein 2 (Skp2) gene expression in gastric carcinoma: modulation of malignant phenotype by Skp2 overexpression, possibly via p27"Cancer Res.. 62. 3819-3825 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Imai Y. et. al.: "CHIP is associated with Parkin, a gene responsible for familial Parkinson's disease, and enhances its ubiquitin ligase activity"Mol. Cell.. 10. 55-67 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Garcia-Femandez et. al.: "Aplidin induces the mitochondrial apoptotic pathway via oxidative stress-mediated JNK and p38 activation and protein kinase Cδ"Oncogene. 21. 7533-7544 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nakamichi I. et. al.: "Formation of Mallory body-like Inclusions and cell death induced by deregulated expression of keratin 18"Mol. Biol. Cell.. 13. 3411-3451 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shimoda K. et. al.: "Tyk2 is required for the induction and nuclear translocation of Daxx which regulates IFN-α-induced suppression of B lymphocyte formation"J. Immunol.. 169. 4707-4711 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Seto Y. et. al.: "Enhanced Th2 cell-mediated allergic inflammation in Tyk2-deficient mice"J. Immunol.. 170. 1077-1083 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kaneko C. et. al.: "Characterization of the mouse gene for the U-box-type ubiquitin ligase UFD2a"Biochem. Biophys. res. Commun.. 300. 297-304 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tomari Sl et. al.: "Glomerular differentiation in p27 and p57 doublemutant metanephroi"Anat. Embryol.. 206. 31-36 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shirane M. et. al.: "Inherent calcineurin inhibitor FKBP38 targets Bcl-2 to mitochondria and inhibits apoptosis"Nature Cell. Biol.. 5. 28-63 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shimoda K. et. al.: "Partial impairment of interleukin-12 (IL-12) and 1L-18 signaling in Tyk2-deficient mice"Blood. 99. 2094-2099 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ishida N. et. al.: "Phosphorylation of p27^<KiP1> on serine 10 is required for its binding to CRM1 and nuclear export"J. Biol. Chem.. 277. 14355-14358 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hara T. et. al.: "Degradotion of p27^<Kip1> at the G0-G1 transition mediated by a Skp2-independent ubiquitination pathway"J. Biol. Chem.. 246. 48937-48943 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Malek N. P. et. al.: "A mouse knock-in model exposes sequential proteolytic pathways that regulate p27^<Kip1> in G1 and S phase"Nature. 413. 323-327 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nagahama H. et. al.: "Spatial and temporal expression, patterns of the cyclin-dependent kinase (CDK) inhibitors p27^<Kip1> and p57^<Kip2> during mouse development"Anat. Embryol.. 203. 77-87 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Minamishima, Y.A. et al.: "Recovery of liver mass without proliferation of hepatocytes after partial hepatectomy in Skp2-deficient mice"Cancer Res.. 62. 995-999 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yoshida, K. et al.: "Involvement of p27^<KIP1> degradation by Skp2 in the regulation of proliferation in response to wounding of corneal epithelium"Invest. Ophthalmol. Vis. Sci.. 43. 364-370 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Koguchi, K. et al.: "Modulation of astrocyte proliferation by cyclin-dependent kinase inhibitor p27Kip1"Glia. 37. 93-104 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ikebe, C. et al.: "Isolation and characterization of a novel F-Box protein Pof10 in fission yeast"Biochem. Biophys. Res. Commun.. 290. 1399-1407 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yamanaka, A. et al.: "Multiple Skp1-related proteins in Caenorhabditis elegans. Diverse patterns of interaction with Cullins and F-box proteins"Curr. Biol.. 12. 267-275 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kanematsu, T. et al.: "Role of the PLC-related, catalytically inactive protein p130 in GABA_A receptor function"EMBO J.. 21. 1004-1011 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Miyamoto A. et al.: "Increased proliferation of B cells and auto-immunity in mice lacking protein kinase Cδ"Nature. 416. 865-869 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Masuda T. et al.: "Clinical and biological significance of S-phase kinase-associated protein 2(Skp2) gene expression in gastric carcinoma : modulation of malignant phenotype by Skp2 overexpression, possibly via p27"Cancer Res.. 62. 3819-3825 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Imai Y.et al.: "CHIP is associated with Parkin, a gene responsible for familial Parkinson's disease, and enhances its ubiquitin ligase activity"Mol. Cell. 10. 55-67 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Garcia-Fernandez. et al.: "Aplidin induces the mitochondrial apoptotic pathway via oxidative stress-mediated JNK and p38 activation and protein kinase Cδ"Oncogene. 21. 7533-7544 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nakamichi I. et al.: "Formation of Mallory body-like Inclusions and cell death induced by deregulated expression of keratin 18"Mol. Biol. Cell. 13. 3411-3451 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Shimoda K. et al.: "Tyk2 is required for the induction and nuclear translocation of Daxx which regulates IFN-α-induced suppression of B lymphocyte formation"J. Immunol.I. 169. 4707-4711 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Seto Y.et al.: "Enhanced Th2 cell-mediated allergic inflammation in Tyk2-deficient mice"J. Immunol. 170. 1077-1083 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kaneko C. et al.: "Characterization of the mouse gene for the U-box-type ubiquitin ligase UFD2a"Biochem. Biophys. Res. Commun.. 300. 297-304 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tomari Sl et al.: "Glomerular differentiation in p27 and p57 double-mutant metanephroi"Anat. Embryol.. 206. 31-36 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Shirane M. et al.: "Inherent calcineurin inhibitor FKBP38 targets Bcl-2 to mitochondria and inhibits apoptosis"Nature Cell Biol.. 5. 28-63 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Shimoda, K. et al.: "Partial impairment of interleukin-12(IL-12)and IL-18 signaling in Tyk2-deficient mice"Blood. 99. 2094-2099 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ishida N. et al.: "Phosphorylation of p27^<Kip1> on serine 10 is required for its binding to CRM1 and nuclear export"J. Biol. Chem.. 277. 14355-14358 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hara, T.: "Degradation of p27^<KiP1> at the G0-G1 transition mediated by a Skp2-independent ubiquitination pathway"J. Biol. Chem. 276. 48937-48943 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Malek, N. P.: "A mouse knock-in model exposes sequential proteolytic pathways that regulate p27^<Kip1> in G1 and S phase"Nature. 413. 323-327 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Tsukiyama, T.: "Down-regulation of p27^<Kip1> expression is required for development and function of T cells"J. Immunol. 166. 304-312 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Nagahama, H.: "Spatial and temporal expression patterns of the cyclin-dependent kinase (CDK) inhibitors p27^<Kip1> and p57^<Kip2> during mouse development"Anat. Embryol. 203. 77-87 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Minamishima, A. Y: "Recovery of liver mass without proliferation of hepatocytes after partial hepatectomy in Skp2-deficient mice"Cancer Res. 62. 995-999 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Miyamoto, A.: "Increased proliferation of B cells and autoimmunity in mice lacking protein kinase Cδ"Nature. (in press). (2002)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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