2005 Fiscal Year Final Research Report Summary
Molecular mechanism of acquisition of drug resistance in lysosomal drug transporter protein-deficient mice
| Project/Area Number |
16570118
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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 |
Functional biochemistry
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| Research Institution | KYUSHU UNIVERSITY |
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Principal Investigator |
TANAKA Yoshitaka Kyushu University, Faculty of Pharmaceutical Sciences, Professor, 大学院・薬学研究院, 教授 (20217095)
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| Co-Investigator(Kenkyū-buntansha) |
FUJITA Hideaki Kyushu University, Faculty of Pharmaceutical Sciences, Reserch Associate, 大学院・薬学研究院, 助手 (80291524)
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| Project Period (FY) |
2004 – 2005
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| Keywords | membrane traffic / lysosome / endosome / transporter / multidrug resistance |
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| Research Abstract |
Despite accumulating evidence that multidrug resistance transporter proteins, P-glycoprotein and MRP, play a part in drug resistance in some clinical cancer, it remains unclear as to why some drugs are sequestrated in an acidic intracellular compartments such as endosomal/lysosomal compartments in some cancer cell lines. LAPTAM4α (lysosomal associated protein transmembrane 4 alpha) was previously identified as a protein that is a nucleoside transporter on intracellular membrane-bound compartments, and mediates a multidrug resistance phenotype in drug-sensitive strains of S.cerevisiae.
To study the importance of LAPTAM4α to the toxicity of center chemotherapy agents, we have generated mice deficient for this protein. LAPTAM4α deficient mice are viable and fertile. Histological and ultrastructural analyses of all tissuses did not reveal abnormalities. Lysosomal properties, such as enzyme activities, lysosomal pH, osmotic stability, density, shape, and subcellular distribution were not changed in comparison with controls. However, we observed the enlargement of late endosomes and lysosomes in embryonic fibroblasts isolated from LAPTAM4α-deficient mice. Similar phenotype was also found in HeLa cells overexpressing GFP-fused LAPTAM4α exogenously. These results, therefore, suggest that LAPTAM4α involves in the formation and function of endosomal/lysosomal compartments.
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