| Project/Area Number |
11694286
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| Research Category |
Grant-in-Aid for Scientific Research (B).
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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 | KYUSHU UNIVERSITY |
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Principal Investigator |
KUWANO Michihiko Dept.of Med.Biochemistry, Grad.Sch.of Med.Sciences KYUSHU UNIVERSITY Professor., 大学院・医学研究院, 教授 (80037431)
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| Co-Investigator(Kenkyū-buntansha) |
UCHIUMI Takeshi Dept.of Med.Biochemistry, Grad.Sch.of Med.Sciences KYUSHU UNIVERSITY Associate Professor, 大学院・医学研究院, 助手 (80253798)
ONO Mayumi Dept.of Med.Biochemistry, Grad.Sch.of Med.Sciences KYUSHU UNIVERSITY Associate Professor, 大学院・医学研究院, 講師 (80128347)
WADA Morimasa Dept.of Med.Biochemistry, Grad.Sch.of Med.Sciences KYUSHU UNIVERSITY Associate Professor, 大学院・医学研究院, 助教授 (20220965)
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| Project Period (FY) |
1999 – 2000
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥8,000,000 (Direct Cost: ¥8,000,000)
Fiscal Year 2000: ¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 1999: ¥4,500,000 (Direct Cost: ¥4,500,000)
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| Keywords | anticancer agents / MRP / MDR1 / efflux pump / cMOAT / MRP2 / YB-1 / Dubin-Johnson syndrome / DNA methylation / ABCトランスポーター / 薬剤排出ポンプ / 抗癌剤感受性 / 遺伝子発現調節 / 遺伝性疾患 |
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| Research Abstract |
The appearance of tumor cells resistant to multiple anticancer agents poses a serious problem during treatment of cancer patients using chemotherapeutic agents. The acquisition of such a multidrug resistance phenotype in cancer cells is often associated with increased expression of cell surface P-glycoprotein(P-gp) encoded by the multidrug resistance 1 (MDR1) gene that functions as a drug efflux pump, and thereby reduces the intracellular concentration of drugs. However, non-P-gp-mediated multidrug resistance is also frequently observed. In the present study, we identified and determined the nucleotide sequence of the cMOAT/MRP2 and MRP3 genes. We then found the participation of the genes on the drug resistance to vincristine, cisplatin, doxorubicin and methotrexate, and etoposide and methotrexate, respectively, by transfection experiment of the cDNAs. We also found that the overexpression of the MDR1 gene in cancer cells was trigared by different mechanisms such as CpG de-methylation, Alu-mediated gene rearrangement and translocation of the transcrptional factor YB-1 among different cancer type. Besides the multidrug resistance, these ATP binding cassette (ABC) transporters have important phisiological functions. We identified four mutations in cMOAT/MRP2 gene in Dubin-Johnson syndrome, human conjugated hyperbilirubinemia, suggesting the function of the cMOAT/MRP2 gene in the transfer of endogenous and exogenous anionic conjugates from hepatocytes into the bile.
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