2002 Fiscal Year Annual Research Report

ポリグルタミン病における異常タンパク質の新規クリアランスシステムの研究

Research Project

Project/Area Number	13480258
Research Institution	Kyushu University
Principal Investigator	中山敬一九州大学, 生体防御医学研究所, 教授 (80291508)
Co-Investigator(Kenkyū-buntansha)	中山啓子東北大学, 大学院・医学系研究科, 教授 (60294972) 畠山鎮次九州大学, 生体防御医学研究所, 助教授 (70294973)
Keywords	MJD / UFD2 / VCP / ポリグルタミン病 / ユビキチン化
Research Abstract	多くの神経変性疾患においては封入体タンパク質の分解機構に破綻がある可能性があることが示唆されている。本研究ではMJD1の分解機構が分子レベルで理解し、それを制御するような遺伝子治療法や低分子化合物の探索することによって、全く新しい作用機序に基づく治療法の開発を期待したものである。またヒトの疾患に類似したモデル動物を作出できることが予想され、根本的治療法の確立に寄与することも目指し、本研究を行っている。異常MJD1タンパク質のクリアランス機構に関与する二つのタンパク質VCPとUFD2がどのようにMJD1をユビキチン・プロテアソーム系によって分解へ導くかという分子メカニズムを明らかにすると同時に、モデルマウスの作製を今年度は行った。 VCPやUFD2はMJD1の分解に関与する分子であるので、細胞内におけるMJD1の過剰蓄積が予想される。そこでこれらノックアウトマウスを観察した。小脳性失調等の神経学的異常の発症を中心に長期観察を行うと共に、発生期から成体までの全身病理検索を行う。さらにノックアウトマウスから初代培養細胞を作製し、その細胞を用いてMJD1のユビキチン化と分解が実際に阻害されているかどうかを検討した。また、それらの細胞に凝集体形成を起こすような変異MJD1を発現したトランスジェニックマウスを作製し、小脳性失調等の神経学的異常の観察を行うと同時に、UFD2ノックアウトマウスとMJD1トランスジェニックマウスを交配することによって、その凝集体形成能や細胞傷害性を検討している。

Research Products
(18 results)

All Other

All Publications (18 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)
[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)
[Publications] Koguchi, K. et al.: "Modulation of astrocyte proliferation by cyclin-dependent kinase inhibitor p27Kip1"Glia. 37. 93-104 (2002)
[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)
[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)
[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)
[Publications] Miyamoto A. et al.: "Increased proliferation of B cells and auto-immunity in mice lacking protein kinase Cδ"Nature. 416. 865-869 (2002)
[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)
[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)
[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)
[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)
[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)
[Publications] Seto Y.et al.: "Enhanced Th2 cell-mediated allergic inflammation in Tyk2-deficient mice"J. Immunol. 170. 1077-1083 (2002)
[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)
[Publications] Tomari Sl et al.: "Glomerular differentiation in p27 and p57 double-mutant metanephroi"Anat. Embryol.. 206. 31-36 (2002)
[Publications] Shirane M. et al.: "Inherent calcineurin inhibitor FKBP38 targets Bcl-2 to mitochondria and inhibits apoptosis"Nature Cell Biol.. 5. 28-63 (2002)
[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)
[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)

2002 Fiscal Year Annual Research Report

ポリグルタミン病における異常タンパク質の新規クリアランスシステムの研究

Principal Investigator

中山 敬一 九州大学, 生体防御医学研究所, 教授 (80291508)

Research Products

[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)

[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)

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

[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)

[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)

[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)

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

[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)

[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)

[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)

[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)

[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)

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

[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)

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

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

[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)

[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)

中山敬一九州大学, 生体防御医学研究所, 教授 (80291508)