2005 Fiscal Year Final Research Report Summary
Functional analyses of VCP protein in neuronal cell death
| Project/Area Number |
16390092
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pathological medical chemistry
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| Research Institution | Kyoto University |
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Principal Investigator |
KAKIZUKA Akira Kyoto University, Graduate School of Biostudies, Professor, 大学院・生命科学研究科, 教授 (80204329)
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| Project Period (FY) |
2004 – 2005
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| Keywords | VCP / neuronal cell death / amino acid modification / oxidation / protein aggregates / AAA ATPase / polyglutmamine |
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| Research Abstract |
Recent molecular analyses on human neurodegenerative disorders have revealed several common features such as accumulation of abnormal protein aggregates, cytoplasmic vacuolizations, neuronal cell death etc. We have analyzed the molecular bases of such disorders especially polyglutamine diseases, and have identified VCP protein, an AAA class ATPase, as a candidate for a sensor for the accumulation of abnormal proteins as well as for a mediator of cell death. Namely, 1)VCP co-localizes with polyglutamine aggregates and other protein aggregates such as Lewy bodies in Parkinson disease, 2)the expression of ATPase activity-negative VCP in nueoronal cells induces ER-derived vacuoles and cell death, 3)several amino acids in VCP are modified by phoshprylations, acetylations and oxidations, 4)such modification can change VCP ATPase activities and its intra cellular localization, 5)especially, oxidized VCP at the 522 cysteine loses its ATPase activities, 6)depending upon the levels of soluble aggregates-prone proteins, VCP can modulate the aggregate formation, indicating dual VCP functions as an aggregate formase and an unfoldase. Further molecular analyses on VCP would lead to clues for further understanding as well as for novel treatments of neurodegenerative disorders such as polyglutamine diseases and Parkinson disease.
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Research Products
(36 results)
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[Journal Article] Polyglutamine-expanded ataxin-3 activates mitochondrial apoptotic pathway by upregulating Bax and downregulating Bcl-xL.2006
Author(s)
Chou, A.H., Yeh, T.H., Kuo, Y.L., Kao, Y.C., Jou, M.J., Hsu, C.Y., Tsai, S.R., Kakizuka, A., Wang, H.L.
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Journal Title
Neurobiol Dis. 21
Pages: 333-345
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Dominant-negative effect of mutation valosin-containing protein in aggresome formation.2006
Author(s)
Kitami, MI., Kitami, T., Nagahama, M., Tagaya, M., Hori, S., Kakizuka, A., Mizuno, Y., Hattori, N.
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Journal Title
FEBS Lett. 580
Pages: 474-478
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] In vivo analysis of the role of aberrant histone deacetylase recruitment and RARα blockade in the pathogenesis of acute promyelocytic leukemia.2006
Author(s)
Matsushita, H., Scaglioni, P.P., Bhaumik, M., Rego, E.M/, Cai, L.F., Majid, S.M., Miyachi, H., Kakizuka, A., Miller, W.H.Jr., Pandolfi, P.P.
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Journal Title
J.ExP.Med. 203
Pages: 821-828
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] α, β-unsaturated ketone is a core moiety of natural ligands for covalent binding to peroxisome proliferator-activated receptor γ.2005
Author(s)
Shiraki, T., Kamiya, N., Shiki, S., Kodama, T.S., Kakizuka, A., Jingami, H.
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Journal Title
J.Biol.Chem. 279
Pages: 51376-51385
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Retinoid signaling competence and RARbeta-mediated gene regulation in the developing mammalian telencephalon.2005
Author(s)
Liao, W.L., Wang, H.F., Tsai, H.C., Chambon, P., Wagner, M., Kakizuka, A., Liu, F.C.
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Journal Title
Dev Dyn. 232
Pages: 887-900
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] ATPase activity of p97/Valosin-containing protein (VCP) is regulated by oxidative modification of the evolutionally conserved cysteine 522 residue in Walker A motif.2005
Author(s)
Noguchi, M., Takata, T., Kimura, Y., Manno, A., Murakami, K., Koike, M., Ohizumi, H., Hori, S., Kakizuka A.
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Journal Title
J.Biol.Chem. 280
Pages: 41332-41341
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Induction of murine leukemia and lymphoma by dominant negative retinoic acid receptor α.2005
Author(s)
Wang, Y.A., Sheng, K., Ishida, Y., Wang, Y., Kakizuka, A., Brooks, S.C.
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Journal Title
Mol.Carcinog. 44
Pages: 252-261
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Molecular clearance of ataxin-3 is regulated by a mammalian E4.2004
Author(s)
Matsumoto, M., Yada, M., Hatakeyama, H., Ishimoto, H., Tanimura, T., Tsuji, S., Kakizuka, A., Kitagawa, M., Nakayama, K.I.
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Journal Title
EMBO J. 23
Pages: 659-669
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Effective treatment of advanced solid tumors by the combination of Arsenic Trioxide and L-Buthionine-Sulfoximine.2004
Author(s)
Maeda, H., Hori, S., Ohizumi, H., Segawa, T., Kakehi, Y., Ogawa, O., Kakizuka, A.
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Journal Title
Cell Death Differ. 7
Pages: 737-746
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Alteration in the cellular response to retinoic acid of a human acute promyelocytic leukemia cell line, UF-1, carrying a patient-derived mutant PML-RARα chimeric gene.2004
Author(s)
Sato, A., Imaizumi, M., Hoshi, Y., Rikiishi, T., Fujii, K., Kizaki, M., Kagechika, H., Kakizuka, A., Hayashi, Y., Iinuma K.
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Journal Title
Leukemia Res. 9
Pages: 959-967
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Physical and functional interaction between dorfin and valosin-containing protein that are colocalized in ubiquitylated inclusions in neurodegenerative disorders.2004
Author(s)
Ishigaki, S., Hishikawa, N., Niwa, J., Iemura, S., Natsume, T., Hori, S., Kakizuka, A., Tanaka, K., Sobue, G.
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Journal Title
J.Biol.Chem. 279
Pages: 51376-51385
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] A mutant ataxin-3 putative-cleavage fragment in brain of Machado-Joseph disease patients and transgenic mice is cytotoxic above a critical concentration.2004
Author(s)
Goti, D., Katzen S.M., Mez, J., Kurtis, N., Kiluk, J., Ben-Haiem, L., Jenkins, N.A, Copeland, N.G., Kakizuka, A., Sharp, A.H., Ross, C.A., Mouton, P.R., Colmer V.
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Journal Title
J.Neuroscience 24
Pages: 10266-10279
Description
「研究成果報告書概要(欧文)」より
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