The study on molecular chaperones as a cancer therapy target
| Project/Area Number |
18592039
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Functional basic dentistry
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| Research Institution | Nagasaki University |
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Principal Investigator |
TAKAYUKI Nemoto Nagasaki University, Graduate School of Biomedical Sciences, Professor (90164665)
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| Co-Investigator(Kenkyū-buntansha) |
BABA Tomomi Nagasaki University, Graduate School of Biomedical Sciences, Assistant Professor (60189727)
YAMADA Shin-ichi Nagasaki University, Graduate School of Biomedical Sciences, Assistant Professor (50380853)
KANATANI Naoko Nagasaki University, Graduate School of Biomedical Sciences, Research Fellow (10380982)
KOBAYAKAWA Takeshi Nagasaki University, Graduate School of Biomedical Sciences, Research Fellow (10153587)
NEMOTO Yuko Nagasaki University, Graduate School of Biomedical Sciences, Associate Professor (10164667)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥3,980,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥480,000)
Fiscal Year 2007: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2006: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Keywords | Molecular chaperone / Hsp90 / Dimer / Isoform / SNP / Two-hybrid system / HSP90 / 熱ショックタンパク質 / ミスセンス変異 |
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| Research Abstract |
Two isoforms of the 90-kDa heat shock protein (Hsp90), i.e., Hsp90α and Hsp90β, are expressed in mammalian cells. Although Hsp90 predominantly exists as a dimer, the dimer-forming potential of human and mouse Hsp90β is less than respective Hsp90α. The 16 amino acid substitutions located in the 561-685 amino-acid region of the C-terminal dimerization domain should be responsible for this impeded dimerization of Hsp90β (Nemoto, et. al., 1995. Eur J Biochem 233: 1-8). The present study was performed to define the amino acid substitutions that cause the impeded dimerization of Hsp90β. Bacterial two-hybrid analysis revealed that, among the 16 amino acids, the conversion from Alasss of Hsp90β to Thr_566 of Hsp90α and that from Met_621 of Hsp90β to A1a_629 of Hsp90α most efficiently reversed the chimeric interaction, and that the inverse changes from those of Hsp90α to Hsp90β primarily explained the impeded dimerization of Hsp90β. A single nucleotide polymorphism (SNP)that causes a missense mutation from Glu to His at position 488 of Hsp90α is observed in Caucasians. A yeast expression system proved that the mutated Hsp90α severely reduced the growth of cells compared with that obtained with wild-type Hsp90α. The Gln488His mutation in MC domain (amino acids 401-732)did not affect the intra-molecular interaction with N-terminal domain (amino acids 1-400). In contrast, the dimeric interaction of Hsp90 mediated by the interaction of MC domains was decreased 68% when both MC domains were mutated. This change was reproduced by Gln488Ala, whereas Gln488Thr maintained the dimeric interaction, which accounted for the reason why Thr could be located at this position in Trap1. Taken together we conclude that the conversion of Thr_<566> and A1a_<629> of Hsp90α to Ala_<558> and Met_<621> primarily responsible for impeded dimerization of Hsp90 and that the SNP causing the missense mutation abrogates the Hsp90 function due to reduced dimerization.
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Report
(3 results)
Research Products
(34 results)
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[Journal Article] Characterization of the glutamyl endopeptidase from Staphylococcus aureus expressed in Escherichia coli2008
Author(s)
Nemoto, TK, Ohara-Nemoto, Y, Ono, T, Kobayakawa, T, Shimoyama, Y, Kimura, S, Takagi, T
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Journal Title
FEBS J 275
Pages: 5723-587
NAID
Description
「研究成果報告書概要(欧文)」より
Related Report
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[Journal Article] A novel in vitro pharmacokinetic/pharmacodynamic model based on two-compartment open model used to simulate serum drug concentration-time profiles2007
Author(s)
Tomita, T, Ohara-Nemoto, Y, Moriyama, H, Ozawa, A, Takeda, Y, Kikuchi, K
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Journal Title
Microbiol. Immunol 51
Pages: 567-575
NAID
Description
「研究成果報告書概要(欧文)」より
Related Report
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[Journal Article] A novel in vitro pharmacokinetic/pharmacodynamic model based on two-compartment open model used to simulate serum drug concentration-time profiles2007
Author(s)
Tomita, T., Ohara-Nemoto, Y., Moriyama, H., Ozawa, A., Takeda, Y., Kikuchi, K.
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Journal Title
Microbiol.Immunol 51(5)
Pages: 567-575
NAID
Related Report
Peer Reviewed
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[Presentation] Impeded dimer formation caused by the SNP Gln488His of human Hsp90α2007
Author(s)
Kobayakawa, T, Yamada, S, Ohara-Nemoto, Y, Mizuno, A, Nemoto, TK
Organizer
30th Japanese Society of Molecular Biology/ 81st Congress of Japanese Biochemical Society
Place of Presentation
Yokohama, Japan
Year and Date
2007-12-15
Description
「研究成果報告書概要(欧文)」より
Related Report
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[Presentation] Dual roles of the prosequence of glutamic acid-specific endopeptidase from Staphylococcus aureus2007
Author(s)
Ono, T, Ohara-Nemoto, Y, Shimoyama, Y, Kimura, S, Takagi, T, Nemoto, TK
Organizer
30th Japanese Society of Molecular Biology and 81st Congress of Japanese Biochemical Society
Place of Presentation
Yokohama, Japan
Year and Date
2007-12-14
Description
「研究成果報告書概要(欧文)」より
Related Report
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[Presentation] Amino acid substitutions observed in human Hsp90 isoforms that impede the dimeric interaction2007
Author(s)
Nemoto, TK, Kobayakawa, T, Ono, T, Yamada, S, Mizuno, A, Baba, TT, Ohara-Nemoto, Y
Organizer
2nd World Conference of Stress and 3rd Cell Stress Society International Congress on Cell Stress Responses in Biology and Medicine
Place of Presentation
Budapest, Hungary
Year and Date
2007-08-25
Description
「研究成果報告書概要(欧文)」より
Related Report
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[Presentation] Pathogenic Factors of Porphyromonas endodontalis2007
Author(s)
Haraga, H, Ohara-Nemoto, Y, Nemoto, TK, Sasaki, M, Tajika, S, Hamada, S, Kimura, S
Organizer
107th ASM General Meeting
Place of Presentation
Toronto, Canada
Year and Date
2007-07-20
Description
「研究成果報告書概要(欧文)」より
Related Report
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