ヒトABCトタンスボーターの遺伝子多型を認識するタンバク品質管理機構の解明

2007 Fiscal Year Annual Research Report

• Project/Area Number: 19659136
• Research Category: Grant-in-Aid for Exploratory Research
• Research Institution: Tokyo Institute of Technology
• Principal Investigator: 石川 智久 Tokyo Institute of Technology, 大学院・生命理工学研究科, 教授 (60193281)
• 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)
• Keywords: タンパク質 / 糖鎖

Research Abstract

ABCG2タンパク質の糖鎖付加・分子内および分子間ジスルフィド結合形成機構を解明する。一般的に、真核細胞において分泌タンパク質や膜タンパク質はリボソーム上で合成され、シャペロンタンパク質の助けを借りて小胞体内でフォールディングされる。タンパク質のフォールディングの重要な鍵を握っているのが、小胞体における様々な翻訳後修飾であり、N-結合型糖鎖付加やジスルフィド結合の形成が代表的である。タンパク質においてジスルフィド結合は、タンパク質構造の安定化に寄与すると考えられているが、我々は、N-結合型糖鎖付加においても重要であると考えている。ヒトABCトランスポーターABCG2の野生型、Cys残基がGly残基に置換されたABCG2、N-結合型糖鎖付加を受ける596番目のAsn残基がGln残基に置換されたABCG2を安定に発現するFlp-In-293細胞株を樹立して、ABCG2蛋白質の発現レベル、ユビキチン化、細胞内分布を解析した。その成果を次の論文に発表した。Wakabayashi, et. al. Intramolecular disulfide bond is a critical checkpoint determining degradative fates of ABC transporter ABCG2 protein. J. Biol. Chem. 282(38):27841-27846,2007.我々の研究により、ABCG2の細胞外ループにあるジスルフィド結合は、小胞体内での蛋白質構造の安定化とN-結合型糖鎖付加において重要であることが明らかになった。

Research Products

• [Journal Article] Unibiquitin-mediated proteasomal degradation of nonsynonymous SNP variants of human ABC transporter ABCG2. (2008)
  • Author(s): Nakagawa H, Tamura A, Wakabayashi K, Hoshijima K, Komada M, Yoshida T, Kometani S, Matsubara T, Mikuriya K, 'Ishikawa T.
  • Journal Title: Biochem. J. 411 Pages: 623-631
  • Peer Reviewed
• [Journal Article] Cellular phototoxicity evoked through the inhibition of human ABC transporter ABCG2 by cyclin-dependent kinase inhibitors in vitro. (2008)
  • Author(s): An R, Hagiya Y, Tamura A, Li S, Saito H, Tokushima D, and Ishikawa T.
  • Journal Title: Photochem. Photobiol. Sci (in press)
  • Peer Reviewed
• [Journal Article] Drug-induced phototoxicity evoked by inhibition of human ABC transporter ABCG2: Development of in vitro high-speed screening systems. (2008)
  • Author(s): Tamura A, An R, Hagiya Y, Hoshijima K, Yoshida T, Mikuriya K, and Ishikawa T.
  • Journal Title: Expert Opinion on Drug Metabolism and Toxicology 4(3) Pages: 255-272
  • Peer Reviewed
• [Journal Article] MRP class of human ABC transporters: Role of glutathione in the function and gene regulation. (2008)
  • Author(s): Toyoda Y, Hagiya Y, Adachi T, Hoshijima K, Kuo MT, Ishikawa T.
  • Journal Title: Xenobiotica (in press)
  • Peer Reviewed
• [Journal Article] Human ABC transporters ABCG2 (BCRP) and ABCG4. (2008)
  • Author(s): Koshiba S, An R, Saito H, Wakabayashi K, Tamura A, and Ishikawa T.
  • Journal Title: Xenobiotica (in press)
  • Peer Reviewed
• [Journal Article] Intramolecular disulfide bond is a critical checkpoint determining degradative fates of ABC transporter ABCG2 protein. (2007)
  • Author(s): Wakabayashi K, Nakagawa H, Tamura A, Koshiba S, Hoshijima K, Komada M, and Ishikawa T.
  • Journal Title: J. Biol. Chem. 282(38) Pages: 27841-27846
  • Peer Reviewed
• [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.
  • Journal Title: Drug Metab. Pharmacokin. 22(6) Pages: 428-440
  • Peer Reviewed
• [Journal Article] Nrf2-dependent and -independent induction of ABC transporters ABCC1, ABCC2, and ABCG2 in HepG2 cells under oxidative strees. (2007)
  • Author(s): Adachi T, Nakagawa H, Chung I, Hagiya Y, Hoshijima K, Noguchi N, Kuo MT and Ishikawa, T.
  • Journal Title: J. Exp. Ther. Oncol. 6 Pages: 335-348
  • Peer Reviewed
• [Journal Article] Development of polyclonal antibodies specific to ATP-binding casstte transporters human ABCG4 and mouse Abcg4: site-specific expression of mouse Abcg4 in brain. (2007)
  • Author(s): Koshiba S, Ito T, Shiota A, Wakabayashi K, Ueda M, Ichinose H, and Ishikawa T.
  • Journal Title: J. Exp. Ther. Oncol. 6 Pages: 321-333
  • Peer Reviewed
• [Journal Article] High-speed screening and quantitative SAR analysis of human ABC transporter ABCG2 for molecular modeling of anticancer drugs to circumvent multidrug resistance. (2007)
  • Author(s): Saito H, Hirano H and Ishikawa T.
  • Journal Title: Mini Rev. Medcin. Chem. 7 Pages: 1009-1018
  • Peer Reviewed
• [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.
  • Journal Title: Biochem. J. 406(1) Pages: 31-40
  • Peer Reviewed
• [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.
  • Journal Title: Biochemistry 46(26) Pages: 7678-7693
  • Peer Reviewed
• [Journal Article] Re-evaluation and functional classification of nonsynonymous single nucleotide polymoiphisms of human ABC transporter ABCG2. (2007)
  • Author(s): Tamura A, Wakabayashi K, Onishi Y, Takeda M, Ikegami Y, Sawada S, Tsuji M, Matsuda Y and Ishikawa T.
  • Journal Title: Cancer Sci. 98(2) Pages: 231-239
  • Peer Reviewed
• [Journal Article] Prediction of drug-induced intrahepatic cholestasis: in vitro screening and QSAR analysis of drugs inhibiting the human bile salt export pump. (2007)
  • Author(s): Sakurai A, Kurata A, Onishi Y, Hirano H and Ishikawa T.
  • Journal Title: Expert Opin. Drug Saf. 6(1) Pages: 71-86
  • Peer Reviewed
• [Journal Article] Identification of two biologically crucial hydroxyl groups of(-)-epigallocatechin gallate in osteoclast culture. (2007)
  • Author(s): Nakagawa H, Hasumi K, Takami M, Aida-Hyugaji S, Woo JT, Nagai K, Ishikawa T and Wachi M.
  • Journal Title: Biochem. Pharmacol. 73(1) Pages: 34-43
  • Peer Reviewed
• [Journal Article] Theoretical studies for molecular modeling of new camptothecin analogues. (2007)
  • Author(s): Aida-Hyugaji S, Nakagawa H, Nomura J, Sakurai M, Nagashima U and Ishikawa T.
  • Journal Title: Croatica Chemica Acta 80(2) Pages: 277-281
  • Peer Reviewed
• [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.
  • Journal Title: Biol. Pharm. Bull. 30(12) Pages: 2371-2375
  • Peer Reviewed
• [Presentation] Genetic Polymorphisms of ABCG2 and ER-associated Degradation (ERAD) Pathway (2008)
  • Author(s): Wakabayashi K, Tamura A, An R, Hoshijima K, Nakagawa H, Ishikawa T.
  • Organizer: 2nd FEBS Special Meeting ABC2008
  • Place of Presentation: Innsbruck, Austria
  • Year and Date: 20080303-05
• [Presentation] Quantitative structure-activity relationship analysis and molecular dynamics simulation to functionally validate nonsynonymous polymorphisms of human ABCG1 (P-glycoprotein/MDR1) (2008)
  • Author(s): Sakurai A, Onishi Y, Liew Ei Leen, Hirano H, Sakurai M, Seigneuret M, Ishikawa T.
  • Organizer: 2nd FEBS Special Meeting ABC2008
  • Place of Presentation: Innsbruck, Austria
  • Year and Date: 20080302-04
• [Presentation] Development of Polyclonal antibodies specific to human ABCG4 and mouse Abcg4: site-specific expression of mouse Abcg4 in brain (2008)
  • Author(s): Koshiba S, Ito T, Wakabayashi K, Ichinose H, Ishikawa T.
  • Organizer: 2nd FEBS Special Meeting ABC2008
  • Place of Presentation: Innsbruck, Austria
  • Year and Date: 20080302-04
• [Presentation] Identification and Inhibitory Characterization of Protein Kinase Inhibitors Based on QSAR Analysis of Human ABC Transporter ABCG2 (2008)
  • Author(s): Saito H, Hirano H, Hirono S, Tokushima D, Ishikawa T.z
  • Organizer: 2nd FEBS Special Meeting ABC2008
  • Place of Presentation: Innsbruck, Austria
  • Year and Date: 20080302-04
• [Presentation] Functional Validate Nonsynonymous Polymorphisms of Human ABCB1 Transporter ABCB1 (P-glycoprotein/MDR1) (2007)
  • Author(s): Sakurai A, Onishi Y, Hirano H, Liew Ei Leen, Obanayama K, Kim G, Sakurai M Ishikawa T
  • Organizer: BMB2007
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-14
• [Presentation] Disulfide Bond Formation Plays a Crucial Role in Protein Stability of Human ABCG2 (2007)
  • Author(s): Wakabayashi K, Nakagawa H, Tamura A, Hoshijima K, Komada M, Ishikawa T
  • Organizer: BMB2007
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-14
• [Presentation] Evidence for ubiquitinqtion and degradation of non-synonymous SNP proteins of human ATP-binding cassette transporter ABCG2 (2007)
  • Author(s): Nakagawa H, Tamura A, Wakabayashi K, Ishikawa T
  • Organizer: BMB2007
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-14
• [Presentation] Transport Mechanism-Based Drug Molecular Design: High-Speed Screening and Quantitative SAR Analysis of ABC Transport ABCG2 to design Novel Anticancer Drugs (2007)
  • Author(s): Saito H, Hirano H, Ikegami Y, Ishikawa T.
  • Organizer: BMB2007
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-11
• [Presentation] Evaluation and Functional Classification of Nonsynonymous Single Nucleotide Polymorphisms of Human ABC Transporter ABCG2 (2007)
  • Author(s): Tamura A, Wakabayashi K, Ikegami Y, Ishikawa T
  • Organizer: BMB2007
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-11
• [Presentation] Critical Role of Human ABC Transporter ABCG2 in Cancer Photodynamic Therapy and Porphyria Risk (2007)
  • Author(s): An R, Tamura A, Onishi Y, Ishiikawa T
  • Organizer: BMB2007
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-11
• [Presentation] Development of polyclonal antibodies specific to ATP-binding cassette transporters human ABCG4 and mouse Abcg4: Site-specific expression of mouse Abcg4 in brain (2007)
  • Author(s): Koshiba S, Ito T, Wakabayashi K, Ichinose H, Ishikawa T.
  • Organizer: BMB2007
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-11
• [Presentation] Liver X receptor ligands include the expression of ATP-binding cassette transporter ABCG2 in human Hepatoma HepG2 cells (2007)
  • Author(s): Adachi T, Nakagawa H, Hoshijima K, Ishikawa T.
  • Organizer: BMB2007
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-11
• [Presentation] Development of Expression system of A Novel Human ATP-Binding Cassette treansporter ABCC11 (2007)
  • Author(s): Toyoda Y, Sakurai A, Yoshiura K, Miwa N, Niikawa N, Ishikawa T.
  • Organizer: BMB2007
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-11
• [Presentation] Nrf2-dependent Induction of ABCC2 and ABCG2 in HepG2 cells under Oxidative Stress (2007)
  • Author(s): Hagiya Y, Adachi T, Nakagawa H, Hoshijima K, Noguchi N, Ishikawa T.
  • Organizer: BMB2007
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-11
• [Presentation] Characterization and Classification of CDK Inhibitors by QSAR Analysis of Human ABC Transporter ABCG2 (2007)
  • Author(s): Saito H, Hirano H, Hirono S, Tokushima D, Ishikawa T
  • Organizer: 8th International ISSX Meeting
  • Place of Presentation: 仙台
  • Year and Date: 2007-10-10
• [Presentation] QSAR Analysis of Human ABC Transporter ABCB1 (P-GP/MDR1): Effect of SNPs on the Substrate Specificity toward CDK Inhibitors (2007)
  • Author(s): Liew Ei Leen, Sakurai A, Hirano H, Seigneuret M, Ishikawa T
  • Organizer: 8th International ISSX Meeting
  • Place of Presentation: 仙台
  • Year and Date: 2007-10-10
• [Presentation] International Standardization of the Methods for In-vitro Funtional Analysis of Drug Transporters (2007)
  • Author(s): Ishikawa T
  • Organizer: 8th International ISSX Meeting (Short Course2)
  • Place of Presentation: 仙台
  • Year and Date: 2007-10-09
• [Presentation] Critical role of human ABC transporter ABCG2 in cancer photodynamic therapy and porphyria risk (2007)
  • Author(s): Ishikawa T, Wakabayashi K, Saito H, Sakurai A, Tamara A
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-04
• [Presentation] Disulfide Bond Formation Plays a Crucial Role in Protein Stability of Human ABCG2 (2007)
  • Author(s): Ishikawa T, Wakabayashi K, Saito H, Sakurai A, Tamara A
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-04
• [Presentation] Evaluation and Functional Classification of Nonsynonymous Single Nucleotide Polymorphisms of Human ABC Transporter ABCG2 (2007)
  • Author(s): Tamura A, Wakabayashi K, Ikegami Y, Ishikawa T
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-04
• [Presentation] Functionally Validate Nonsynonymous Polymorphisms of Human ABC Transporter ABCB1 (P-glycoprotein/MDR1) (2007)
  • Author(s): Sakurai A, Tamura A, Saito H, Wakabayashi K, Sakaeda T, Ishikawa T
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-04
• [Presentation] Expression of ABC transporter mRNA in Cololectal cancer Specimen (2007)
  • Author(s): Satake K, Ikegami Y, Sano K, Yamane Y, Ishikawa T
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-04
• [Presentation] High-Speed Screening and QSAR Analysis of Human ABC Transporter ABCG2 for Molecular Modeling of Anticancer Drugs (2007)
  • Author(s): Saito H, Tamura A, Wakabayashi K, Sakurai A, Ishikawa T
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-04
• [Presentation] A New Strategy of High-Speed Screening and Quantitative SAR Analysis to Evaluate Human ABC Transporter ABCG2-Drug Interactions (2007)
  • Author(s): Saito H, Hirano H, Osumi M, , Ishikawa T
  • Organizer: Gordon Research Conference on Drug Metabolism
  • Place of Presentation: NH U.S.A.
  • Year and Date: 2007-07-11
• [Presentation] Functional validation of genetic plymorphisms of ABCB1(P-glycoprotein/MDR1): Quantative SAR analysis and moleculae dynamic simulation (2007)
  • Author(s): Sakurai A, Onishi Y, Liew Ei Leen, Hirano H, Sakurai M, Seigneuret M, Ishikawa T,
  • Organizer: Gordon Research Conference on Drug Metabolism
  • Place of Presentation: NH U.S.A.
  • Year and Date: 2007-07-11
• [Presentation] Re-evalution and functional classification of nonsynonymous single nucleotide polymorphisms of human ABC transporter ABCG2 (2007)
  • Author(s): Tamura A, Wakabayashi K, Takeda M, Ikegami Y, Ishikawa T
  • Organizer: 4th World Conference on Drug Absorption, Transport and Delivery
  • Place of Presentation: 金沢
  • Year and Date: 2007-06-21
• [Presentation] Functional validation of genetic polymorphisms of ABCB1 (P-glycoprotein/MDR1): The funtional impact of tetra-allelic SNPs 2677G>T, A, or C (2007)
  • 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
• [Presentation] Nrf2/Keap1系によって発現制御を受けるABCトランスポーターの探索 (2007)
  • Author(s): Hagiya H, et. al.
  • Organizer: 第2回トランスポーター研究会
  • Place of Presentation: 東京
  • Year and Date: 2007-06-09
• [Presentation] ヒトABCトランスポーターABCG2のポルフィリン輸送における薬理学的役割:薬物によるABCG2の阻害と光毒性との関係 (2007)
  • Author(s): Adachi T, Nakagawa H, Chung I, Kuo M.T, Ishikawa T.
  • Organizer: 第34回ポルフィリン研究会
  • Place of Presentation: 東京
  • Year and Date: 2007-05-12
• [Presentation] Development of specific antibodies against mouse ATP-binding cassette transporter Abcg4 and expression of Abcg4 in Sf9 insectcells. (2007)
  • Author(s): Koshiba S, Ito T, Ichinose H., Ishikawa, T.
  • Organizer: AACR Annual Meeting 2007
  • Place of Presentation: Los Angeles, U.S.A
  • Year and Date: 2007-04-16
• [Presentation] Nrf2-dependent and indepenndent transcriptional upregulation of ABCC1, ABCC2, ABCC3, and ABCG2 genes in HepG2 cells. (2007)
  • Author(s): Adachi T, Nakagawa H, Chung I, Kuo M. T, Ishikawa T.
  • Organizer: AACR Annual Meeting 2007
  • Place of Presentation: Los Angeles, U.S.A
  • Year and Date: 2007-04-16
• [Presentation] ヒトABCトランスポーターABCG2のポルフィリン輸送における薬理学的役割:薬物によるABCG2の阻害と光毒性との関係 (2007)
  • Author(s): Adachi T, Nakagawa H, Chung I, Kuo M.T, Ishikawa T.
  • Organizer: 第34回ポルフィリン研究会
  • Place of Presentation: Los Angeles, U.S.A.
  • Year and Date: 2007-04-16
• [Book] トランスポーター科学最前線 (2008)
  • Author(s): 辻 彰, 田村 藍, 若林 香奈子, 齊藤 光, 石川 智久, 他28名
  • Total Pages: 374
  • Publisher: 京都 廣川書店
• [Remarks]
  • URL: http://www.ishikawa-lab.bio.titech.ac.jp
• [Remarks]
  • URL: http://www.humanABC.bio.titech.ac.jp