2006 Fiscal Year Final Research Report Summary
Nano-scale analysis of the drug transport mechanism of MRP1
| Project/Area Number |
17590272
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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 |
Pathological medical chemistry
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| Research Institution | Kagoshima University |
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Principal Investigator |
FURUKAWA Tatsuhiko Kagoshima University, Graduate School of Medical and Dental Sciences, Associate Professor, 大学院医歯学総合研究科, 助教授 (40219100)
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| Project Period (FY) |
2005 – 2006
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| Keywords | MRP1 / LTC4 / photoaffinity labeling / Glutathione / ABC transporter / Nucleotide binding domain / tryptic Fragment / SN-38 |
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| Research Abstract |
Trypsin digests a cytoplasmic loop between the 17th membrane spanning domain and the C-terminal NBD of MRP1. We found that the limited digestion was inhibited in the presence of glutathione (GSH). The inhibitory effect of GSH enhanced by adding of AG-A or Vincristine. The L_0/ICL3 domain was indispensable for the inhibitory effect of GSH. These data suggested GHS interact with the L_0/ICL3 domain and induce a structural change of the C-terminal part of MRP1.
We found conserved pairs of Glutamine (507th and 1157th AA(amino acid)) and Glycine (511th and 1161st AA) in the ICL5 (intracellular loop) and the ICL7. These mutant proteins of MRP1 did not have significant structural changes, however lost the transport activity of LTC_4 and could not be photoaffinity labeled with azidoAG-A. The ICL5 mutant MRP1 protein had ATP binding activity of NBD1 but did not that of NBD2. The ICL7 mutant MRP1 protein had lost ATP binding activity in both NBDs. These data suggested that these conserved AAs have important roles in recognition of GSH, binding of ATP and ATPase activity.
Some substrates which can be transported with MRP1 without GSH had been reported. However the difference between GSH dependent and independent transport with MRP1 was not clear. SN-38 can be transported with MRP1 in the absence of GSH. We showed one L_0/ICL3 mutant MRP1 which could not transport LTC_4, could transport SN-38. This data suggested the substrates recognition sites of MRP1 may be different between GSH dependent and independent transport at least in part. We also demonstrated that it might be possible to distinguish between GHS dependent or independent substrate on the base of chemical structures.
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[Journal Article] Copper-transporting P-type ATPase, ATP7A, Confers Multidrug Resistance and its Expression is Related to Resistance to SN-38 in Clinical Colon Cancer.2007
Author(s)
Owatari S, Akune S, Komatsu M, Ikeda R, Firth SD, Che XF., Yamamoto M, Tsujikawa K, Kitazono M, Ishizawa T, Takeuchi T, Aikou T, Mercer FBJ, Akiyama S, Furukawa T.
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Journal Title
Cancer Research 67(10)
Pages: 4860-4868
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Protection against DNA damage-induced apoptosis by the angiogenic factor thymidine phosphorylase lase2006
Author(s)
Jeung HC, Che XF, Haraguchi M, Zhao HY, Furukawa T, Gotanda T, Zheng CL, Tsuneyoshi K, Sumizawa T, Roh JK, Akiyama S.
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Journal Title
FEBS Letter 580(5)
Pages: 1294-1302
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] 2-Deoxy-D-ribose inhibits hypoxia-induced apoptosis by suppressing the phosphorylation of p38 MAPK.2006
Author(s)
Ikeda R, Che XF, Ushiyama M, Yamaguchi T, Okumura H, Nakajima Y, Takeda Y, Shibayama Y, Furukawa T, Yamamoto M, Haraguchi M, Sumizawa T, Yamada K, Akiyama S.
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Journal Title
Biochem. Biophys. Res. Commun. 342(1)
Pages: 280-285
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Overexpression of survivin in primary ATL cells and sodium arsenite induces apoptosis by down-regulating survivin expression in ATL cell lines.2006
Author(s)
Che XF., Zheng CL., Owatari, S., Mutoh M., Gotannda, T., Jeung HC, Furukawa T., Ikeda R., Yamamoto M., Haraguchi M., Arima N., Akiyama SI.
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Journal Title
Blood 107(12)
Pages: 4880-4887
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Molecular basis for the involvement of thymidine phosphorylase in cancer invasion.2006
Author(s)
Gotanda T, Haraguchi M, Tachiwada T, Shinkura R, Koriyama C, Akiba S, Kawahara M, Nishiyama K, Sumizawa T, Furukawa T, Mimata H, Nomura Y, Akiyama S, Nakagawa M.
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Journal Title
Int. J. Mol. Med. 17(6)
Pages: 1085-1091
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] The small heat shock protein alpha B-crystal lin inhibits differentiation-induced caspase 3 activation and myogenic differentiation.2006
Author(s)
Ikeda R, Yoshida K, Ushiyama M, Yamaguchi T, Iwashita K, Fukagawa T, Shibayama Y, Oiso S, Takeda Y, Kariyazono H, Furukawa T, Nakamura K, Akiyama S, Inoue I, Yamada K.
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Journal Title
Biol. Pharm. Bull. 29(9)
Pages: 1815-1819
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Characterization of MVP and VPARP assembly into vault ribonucleoprotein complexes.2005
Author(s)
Zheng CL., Su nizawa T., Che XF., Tsuyama S., Furukawa T., Haraguchi M., Gao H., Gotanda T., Jueng HC., Murata F., Akiyama S.
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Journal Title
Biochem. Biophys. Res. Commun. 326(1)
Pages: 100-107
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] GSH inhibits trypsinization of the C-terminal half of human MRP1.2005
Author(s)
Ren X-Q., Furukawa T., Nakajima Y., Takahashi H., Aoki S., Sumizawa, T., Haraguchi M., Kobayashi M., Chijiwa K., Akiyama S.
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Journal Title
J. Biol. Chem. 280(7)
Pages: 6231-6237
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Cepharanthine potently enhances the sensitivity of anticancer agents in K562 cells.2005
Author(s)
Ikeda R., Che XF., Yamaguchi T., Ushiyama M., Zheng CL., Okumura H., Takeda Y., Shibayama Y., Nakamura K., Jeung HC., Furukawa T., Sumizawa T., Haraguchi M., Akiyama S., Yamada K.
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Journal Title
Cancer Sci. 96(6)
Pages: 372-376
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] MRP1 mutated in the L_0 region transports SN-38 but not leukotriene C_4 or estradiol-17 (beta-D-glucuronate).2005
Author(s)
Noguchi T., Ren XQ., Aoki S., Igarashi Y., Che XF.Nakajima Y, Takahashi H., Mitsuo R., Tsujikawa K., Sumizawa T., Haraguchi M., Kobayashi M., Goto S., Kanehisa M., Aikou T., Akiyama S., Furukawa T.
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Journal Title
Biochem Pharmacol 70 (7)
Pages: 1056-1065
Description
「研究成果報告書概要(欧文)」より
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