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

2009 Fiscal Year Annual Research Report

• Project/Area Number: 19659136
• Research Institution: The Institute of Physical and Chemical Research
• 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)
• 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)。

Research Products

• [Journal Article] Production of cells with targeted integration of gene variants of human ABC transporter for stable and regulated expression using the F1p recombinase system (2010)
  • Author(s): Wakabayashi-Nakao K, Tamura A, Koshiba S, Nakagawa H, Ishikawa T.
  • Journal Title: Methods in Molecular Biology (印刷中)
  • Peer Reviewed
• [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.
  • Journal Title: FASEB Journal 23 Pages: 2001-2013
  • Peer Reviewed
• [Journal Article] Disruption of N-linked glycosylation enhances ubiquitin-mediated proteasomal degradation of human ATP-binding cassette transporter ABCG2 (2009)
  • Author(s): Nakagawa H, Wakabayashi-Nakao K, Tamura A, Toyoda Y, Koshiba S, Ishikawa T.
  • Journal Title: FEBS Journal 276 Pages: 7237-7252
  • Peer Reviewed
• [Journal Article] Quality control of human ABCG2 protein in the endoplasmeic reticulm : ubiquitination and proteasomal degradation (2009)
  • Author(s): Wakabayashi-Nakao K, Tamura A, Furukawa T, Nakagawa H, Ishikawa T.
  • Journal Title: Advances in Drug Delivery Review 61 Pages: 66-72
  • Peer Reviewed
• [Journal Article] Major SNP(Q141K)variant of human ABC transporter ABCG2 undergoes lysosomal and proteosomal degradations (2009)
  • Author(s): Furukawa T, Wakabayashi K, Tamura A, Nakagawa H, Morishima Y, Osawa Y, Ishikawa T.
  • Journal Title: Pharmaceutical Research 26 Pages: 469-479
  • Peer Reviewed
• [Journal Article] 個別化医療」の市場とわが国における課題克服 (2009)
  • Author(s): 石川智久
  • Journal Title: MedicalBio 別冊(7月) Pages: 24-31
• [Journal Article] 薬物トランスポーターのSNP診断 (2009)
  • Author(s): 石川智久
  • Journal Title: MedicalBio 別冊(7月) Pages: 78-83
• [Presentation] Genetic Polymorphisms of ABC Transporters in Cancer Chemotherapy : Development of SmartAmp2 Method for Clinical Genetic Testing (2010)
  • Author(s): Ishikawa, T., Aw, W., Ledhava, A., Hayashizaki, Y.
  • Organizer: AACR Conference on ranslational Cancer Medicine 2010(Europe)
  • Place of Presentation: Amsterdam、オランダ
  • Year and Date: 2010-03-23
• [Presentation] Pharmacogenomics of human ABC transporters : from functional validation to clinical application (2010)
  • 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
• [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
• [Presentation] Genetic polymorphism in human ABC transporter ABCC11 gene : Potential association between earwax and breast cancer risk (2009)
  • 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
• [Presentation] Monomeric non-glycosylated form of human ATP-binding cassette transporter ABCG2 is the most fragile in culture cells (2009)
  • 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
• [Presentation] Pharmacogenomics of human ABC transporters : From functional SNP analysis to application of SmartAmp2 method in clinical research (2009)
  • Author(s): Ishikawa, T., Lezhava, A., Hayashizaki, Y.
  • Organizer: 24^<th> JSSX Annual Meeting
  • Place of Presentation: 京都
  • Year and Date: 2009-11-25
• [Presentation] Association between the wild type allele in human ABC transporter ABCC11 gene and breast cancer risk : Evaluation by the SmartAmp2 method (2009)
  • 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
• [Presentation] N-linked glycosylation stabilizes the de novo synthesized human ABC transporter ABCG2 protein (2009)
  • Author(s): Nakagawa, H., Wakabayashi-Nakao, K., Tamura, A., Ishikawa, T.
  • Organizer: 日本癌学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2009-10-03
• [Presentation] SNP(G538A)of the human ABC transporter ABCC11 correlates with earwax type and breast cancer risk (2009)
  • Author(s): Ishikawa, T., Nakagawa, H., Toyoda, Y., Saito, H., Hayashizaki, Y.
  • Organizer: 日本癌学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2009-10-01
• [Presentation] 薬物トランスポーターの遺伝子多型の機能解析:国際標準化からFDA白書まで (2009)
  • Author(s): 石川智久
  • Organizer: イノベーションジャパン
  • Place of Presentation: 東京
  • Year and Date: 2009-09-16
• [Presentation] Human ABC transporter ABCC11 : genetic polymorphisms and molecular mechanisms determining the type of earwax (2009)
  • Author(s): Ishikawa, T., Toyoda, Y., Yoshiura, K., Niikawa, N.
  • Organizer: The 5^<th> Takeda Science Foundation Symposium on PharmaSciences
  • Place of Presentation: 東京
  • Year and Date: 2009-05-26
• [Presentation] Biochemical characterization of human ABC transporter ABCC11 : Its genetic polymorphism determining earwax type (2009)
  • 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
• [Presentation] Impact of Major Non-synonymous SNP(Q141K)on Proteolysis of Human ABC Transporter ABCG2 via Lysosomal and Ubiquitin-mediated Proteasomal Degradation Pathways (2009)
  • Author(s): Furukawa, T., Wakabayashi-Nakao, K., Tamura, A., Nakagawa, H., Ishikawa, T.
  • Organizer: The 50^<th> Takeda Science Foundation Symposium on PharmaSciences
  • Place of Presentation: 東京
  • Year and Date: 2009-05-25
• [Presentation] FDA Critical Path Transporter Workshop の報告 (2009)
  • Author(s): 石川智久
  • Organizer: 第23回日本薬物動態学会ワークショップ
  • Place of Presentation: 東京
  • Year and Date: 2009-04-24