ヒトABCトランスポーターの遺伝子多型を認識するタンパク品質管理機構の解明
Project/Area Number |
19659136
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Research Category |
Grant-in-Aid for Challenging Exploratory Research
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Allocation Type | Single-year Grants |
Research Field |
Applied pharmacology
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Research Institution | The Institute of Physical and Chemical Research (2009) Tokyo Institute of Technology (2007-2008) |
Principal Investigator |
石川 智久 The Institute of Physical and Chemical Research, オミックス基盤研究領域, 客員主管研究員 (60193281)
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Co-Investigator(Kenkyū-buntansha) |
中川 大 東京工業大学, 大学院・生命理工学研究科, 助教 (40397039)
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Project Period (FY) |
2007 – 2009
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Project Status |
Completed (Fiscal Year 2009)
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Budget Amount *help |
¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2009: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2008: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2007: ¥1,200,000 (Direct Cost: ¥1,200,000)
|
Keywords | タンパク質 / 糖鎖 / 遺伝子多型 / トランスポーター / 翻訳後修飾 |
Research Abstract |
ヒトABC(ATP-Binding Cassette)トランスポーターは、細胞内代謝物の輸送や癌の抗癌剤耐性に関与する重要な膜タンパク質である。平成21年度我々は、ヒトABCトランスポーターABCC11のSNPの中でも、タンパク質の安定性が変化し発現レベルが変わるSNPに注目し、その多型を認識するタンパク質品質管理機構の細胞内分子メカニズムを解明した。タンパク質の発現レベルが著しく低いABCC11の非同義置換G180R(Gly180Arg)SNPバリアントは、ユビキチン化を経て分解されていることを証明した(Toyoda Y, et al.Earwax, osmidrosis, and breast cancer : why does one SNP(538G>A)in the human ABC transporter ABCC11 gene determine earwax type? FASEB J.23(6):2001-2013.2009)。一方、ABCG2の糖鎖付加は複数のステップを経て進行すると考えられる。それぞれのステップに特異的阻害剤をABCG2発現細胞に作用させ、ABCG2の発現量・発現部位(形質膜・細胞内)・輸送機能等の変化を解明した。その結果、ABCG2蛋白質の安定性において、ジスルフィド結合に加えて、N-結合性糖鎖が重要であることが判った(Nakagawa H, et al.Disruption of N-linked glycosylation enhances ubiquitin-mediated proteasomal degradation of human ATP-binding cassette transporter ABCG2. FEBS J.276(24),7237-7252,2009)。
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Report
(3 results)
Research Products
(94 results)
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[Journal Article] Earwax, osmidrosis, and breast cancer why does one SNP(538G>A) in the human ABC transporter ABCC11 gene determine earwax type?2009
Author(s)
Toyoda Y, Sakurai A, Mitani Y, Nakashima M, Yoshiura K, Nakagawa H, Sakai Y, Ota I, Lezhava A, Hayashizaki Y, Niikawa N, Ishikawa T.
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Journal Title
FASEB Journal 23
Pages: 2001-2013
Related Report
Peer Reviewed
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[Journal Article] In vitro evaluation of photosensitivity risk related to genetic polymorphisms of human ABC transporter ABCG2 and inhition by drugs.2007
Author(s)
Tamura A, Onishi Y, An R, Koshiba S, Wakabayashi K, Hoshijima K, Priebe W, Yoshida T, Kometani, S, Matsubara T, Mikuriya K, and Ishikawa, T.
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Journal Title
Drug Metab. Pharmacokin. 22(6)
Pages: 428-440
Related Report
Peer Reviewed
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[Journal Article] Multidrug resistance-associated protein 9 (ABCC12) is present in sperm.2007
Author(s)
Ono N, van der Heiden I, Schffer GL, van de Wetering, van Deenter E, de Haas M, Boerke A, Gadella BM, de Rooij DG, Neefjes JJ, Groothuis TAM, Oomen L, Brocks L, Ishikawa T, and Borst P.
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Journal Title
Biochem. J. 406(1)
Pages: 31-40
Related Report
Peer Reviewed
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[Journal Article] Quantitative SAR analysis and molecular dynamic simulation to functionally validate nonsynonymous polymorphisms of human ABC transporter ABCB1.2007
Author(s)
Sakurai A, Onishi Y, Hirano H, Seigneuret M, Obanayama K, Kim G, Liew EL, Sakaeda T, Yoshiura K, Niikawa N, Sakurai M and Ishikawa T.
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Journal Title
Biochemistry 46(26)
Pages: 7678-7693
Related Report
Peer Reviewed
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[Journal Article] Association of cumulative cyclosporine dose with its irreversible nephrotoxicity in Japanese patients with pediatric-onset autoimmune diseases.2007
Author(s)
Nakamura T, Nozu K, Iijima K, Yoshikawa N, Moriya Y, Yamamori M, Kako A, Matsuo M, Sakurai A, Okamura N, Ishikawa T, Okumura K, Sakaeda T.
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Journal Title
Biol. Pharm. Bull. 30(12)
Pages: 2371-2375
NAID
Related Report
Peer Reviewed
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[Presentation] Pharmacogenomics of human ABC transporters : from functional validation to clinical application2010
Author(s)
Ishikawa, T., Aw, W., Saito, H., Toyoda, Y., Nakagawa, H., Lezhava, A., Hayashizaki, Y.
Organizer
3^<rd> FEBS Special Meeting on ABC Proteins
Place of Presentation
Innsbruck, Austria
Year and Date
2010-03-04
Related Report
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[Presentation] Earwax, osmidrosis, and breast cancer : why does one SNP(538G>A)in the human ABC transporter ABCC11 gene determine earwax type?2010
Author(s)
Toyoda, Y., Nakagawa, H., Aw, W., Lezhava, A., Hayashizaki, Y., Niikawa, N., Ishikawa, T.
Organizer
3^<rd> FEBS Special Meeting on ABC Proteins
Place of Presentation
Innsbruck, Austria
Year and Date
2010-03-04
Related Report
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[Presentation] Genetic polymorphism in human ABC transporter ABCC11 gene : Potential association between earwax and breast cancer risk2009
Author(s)
Toyoda, Y., Ota, I., Ishikawa, T., Lezhava, A., Hayashizaki, Y., Ishikawa, T.
Organizer
日本分子生物学会年会
Place of Presentation
横浜
Year and Date
2009-12-09
Related Report
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[Presentation] Monomeric non-glycosylated form of human ATP-binding cassette transporter ABCG2 is the most fragile in culture cells2009
Author(s)
Nakagawa, H., Wakabayashi-Nakao, K., Tamura, A., Koshiba, S., Toyoda, Y., Ishikawa, T.
Organizer
日本分子生物学会年会
Place of Presentation
横浜
Year and Date
2009-12-09
Related Report
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[Presentation] Association between the wild type allele in human ABC transporter ABCC11 gene and breast cancer risk : Evaluation by the SmartAmp2 method2009
Author(s)
Ishikawa, T., Toyoda Y, Ota, I., Lezhava, A., Ishikawa, T., Hayashizaki, Y.
Organizer
AACR Special Conference in Breast Cancer Research
Place of Presentation
San Diego, USA
Year and Date
2009-10-15
Related Report
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[Presentation] Biochemical characterization of human ABC transporter ABCC11 : Its genetic polymorphism determining earwax type2009
Author(s)
Toyoda, Y., Nakagawa, H., Nakashima, M., Yoshiura, K., Niikawa, N., Ishikawa, T.
Organizer
The 5^<th> Takeda Science Foundation Symposium on PharmaSciences
Place of Presentation
東京
Year and Date
2009-05-25
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[Presentation] Functional validation of genetic polymorphisms of ABCB1 (P-glycoprotein/MDR1): The funtional impact of tetra-allelic SNPs 2677G>T, A, or C2007
Author(s)
Sakurai A, Onishi Y, Liew Ei Leen, Hirano H, Sakurai M, Seigneuret M, Ishikawa T,
Organizer
4th World Conference on Drug Absorption, Transport and Delivery
Place of Presentation
金沢
Year and Date
2007-06-21
Related Report
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