2005 Fiscal Year Final Research Report Summary
Molecular structure and functional regulation of ATP-binding cassette transporters
| Project/Area Number |
13142208
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | Kyushu University |
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Principal Investigator |
WADA Morimasa Kyushu University, Department of Medical Biochemistry, Associate Proffesor, 大学院医学研究院, 助教授 (20220965)
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| Project Period (FY) |
2001 – 2005
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| Keywords | ABC membrane protein / Effulux pump / Chimeric proteins / Substrate affinity / Colorectal cancer risk / ABCC2 / ABCB1 |
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| Research Abstract |
(1) Mechanism of substrate recognition : By constructing of ABCC1/ABCC2 chimeric proteins and examining their the kinetic properties for LTC_4 transport in inside-out membrane vesicles, we have obtained the results suggesting that Membrane Spanning Domain (MSD)1 are involved in substrate affinity and that the COOH-terminal half is exchangeable between two proteins. Because, basic and/or charged residues in MSD2 and MSD3 but not in MSD1 have been reported repeatedly to be involved in substrate binding, our results shows that portion contributing in substrate affinity would be different from that of substrate binding itself.
(2) Sorting mechanisms for intracellular localization : We narrowed down the region participating in determination of apical-basolateral localization to the second membrane spanning domain 2(MSD2)and surrounding region.
(3) To evaluate the effect of ABCB1 in intestinal tumorigenesis directly, we generated Abcbla-disrupted mice with an Apc^<min/+> background, an animal model for human familial adenomatous polyposis, and examined whether polyp formation were affected by the absence of functional ABCB1. The number and size of intestinal polyps in Abcbla^<-/->, Apc^<min/+> mice was significantly smaller than the number in Abcbla^<+/+>, Apc^<Min/+> mice. We then analyzed association between genetic variations in the ABCBI gene and cororectal cancer risk. By case-control study using 460 colorectal cancer patients and 783 healthy volunteers, we obtained the results indicating that the cancer risk of individuals who's genetic background is associated with low ABCB1 level is half of the individuals with lower ABCB1 genetic background.
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[Journal Article] The genetic polymorphism of drug transporters : functional analysis approaches.2004
Author(s)
Ishikawa, T., Tsuji, A., Inui, K., Sai, Y., Anzai, N., Wada, M., Endou, H., Sumino, Y.
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Journal Title
Pharmacogenomics 5
Pages: 1-33
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Dubin-Johnson-like black liver with normal bilirubin level.2004
Author(s)
Kobayashi, Y., Ishihara, T., Wada, M., Kajihara, S., Araki, J., Mifuji, R., Itani, T., Kuroda, M., Urawa, F., Kaito, M., Adachi, Y.
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Journal Title
Journal of Gastroenterology 39
Pages: 892-895
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Genetic polymorphism at the 5' regulatory region of MDR1 and its association with inter-individual variation of expression level in colon.2003
Author(s)
Taniguchi, S., Mochida.Y., Uchiumi, T., Tahira, T., Hayashi, K., Takagi, K., Shimada, M., Maehara, Y., Kuwano, H., Kono, S., Nakano, H., Kuwano, M., Wada, M.
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Journal Title
Molecular Cancer Therapeutics 2
Pages: 1351-1359
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] The role of P-glycoprotein in intestinal tumorigenesis : disruption of mdrla suppresses polyp formation in ApcMin/+ mice.2003
Author(s)
Mochida, Y., Taguchi, K., Taniguchi, S., Tsuneyoshi, M., Kuwano, H., Tsuzuki, T., Kuwano, M., Wada, M.
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Journal Title
Carcinogenesis 24
Pages: 1219-1224
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Identification of Domains Participating in the Substrate Specificity of the Multidrug Resistance Proteins, MRP1 and MRP2.2003
Author(s)
Konno, T., Ebihara, T., Hisaeda, K, Uchiumi, T., Nakamura, T., Shirakusa, T., Kuwano, M., Wada, M.
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Journal Title
Journal of Biological Chemistry 278
Pages: 22908-22917
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] The Basic and Clinical Implication of ABC transporters, YB-1 and Angiogenesis in Human Malignancies.2003
Author(s)
Kuwano, M., Uchiumi, T., Hayakawa, H., Ono, M., Wada, M., Izumi, H., Kohno, K.
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Journal Title
Cancer Science 94
Pages: 9-14
Description
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[Journal Article] Trafficking and functional defects by mutations of the ATP-binding domains in MRP2 in patients with Dubin-Johnson syndrome.2002
Author(s)
Hashimoto, K., Uchiumi, T., Konno, T., Ebihara, T., Nakamura, T., Wada, M., Sakisaka, S., Maniwa, F., Amachi, T., Ueda, K., Kuwano M.
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Journal Title
Hepatology 36
Pages: 1236-1245
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] The Association of DAP-kinase Hypermethylation with Early Recurrence in Superficial Bladder Cancers2002
Author(s)
Tada, Y., Wada, M., Taguchi, K., Mochida, Y., Kinugawa, N., Tsuneyoshi, M., Naito, S., Kuwano, M.
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Journal Title
Cancer Research 62
Pages: 4048-4053
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Increased expression of multidrug resistance-associated proteinsin bladder cancer during clinical course and drug resistance to doxorubicin.2002
Author(s)
Tada, Y., Wada, M., Migita, T., Nagayama, J., Hinoshita, E., Mochida, Y., Maehara, Y., Tsuneyoshi, M., Kuwano, M., Naito, S.
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Journal Title
International Journal of Cancer 98
Pages: 630-635
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Retrovirus insertion and transcriptional activation of the multidrug resistance (mdrla) gene in leukemias treated by a chemotherapeutic agent in vivo.2001
Author(s)
Nagayama, J., Iino, M., Tada, Y., Kusaba, H., Kiue, A., Ohshima, K., Kuwano, M., Wada, M.
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Journal Title
Description
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