The small GTPases Rab5 and RalA regulate intracellular traffic of P-glycoprotein
- 作者：Dong Fu ; Ellen M. van Dam ; Adam Brymora ; Iain G. Duggin ; Phillip J. Robinson ; Basil D. Roufogalis
- 关键词：P-glycoprotein ; endocytosis ; exocytosis ; Rab5 ; RalA ; multidrug resistance in cancer
- 刊名：Biochimica et Biophysica Acta (BBA)/Molecular Cell Research
- 出版年：2007
- 期刊代码：20_01674889
- 类别：bio
- 出版时间：July 2007
- 卷：1773
- 期：7
- 页码：1062-1072
- 文件大小：1756 K
摘要
P-glycoprotein (P-gp) is a plasma membrane glycoprotein that can cause multidrug resistance (MDR) of cancer cells by acting as an ATP-dependent drug efflux pump. The regulatory effects of the small GTPases Rab5 and RalA on the intracellular trafficking of P-gp were investigated in HeLa cells. As expected, overexpressed enhanced green fluorescent protein (EGFP)-tagged P-gp (P-gp-EGFP) is mainly localised to the plasma membrane. However, upon cotransfection of either dominant negative Rab5 (Rab5-S34N) or constitutively active RalA (RalA-G23V) the intracellular P-gp-EGFP levels increased approximately 9 and 13 fold, respectively, compared to control P-gp-EGFP cells. These results suggest that Rab5 and RalA regulate P-gp trafficking between the plasma membrane and an intracellular compartment. In contrast, coexpression of constitutively active Rab5 (Rab5-Q79L) or dominant negative RalA (RalA-S28N) had no effect on the localisation of P-gp-EGFP. Furthermore, the intracellular accumulation of daunorubicin, a substrate for P-gp, increased significantly with an increased intracellular localisation of P-gp-EGFP. These results imply that it may be possible to overcome MDR by controlling the plasma membrane localisation of P-gp.