The small GTPases Rab5 and RalA regulate intracellular traffic of P-glycoprotein

Fu, D; van Dam, EM; Brymora, A; Duggin, IG; Robinson, PJ; Roufogalis, BD

The small GTPases Rab5 and RalA regulate intracellular traffic of P-glycoprotein

Fu, D van Dam, EM Brymora, A Duggin, IG

Robinson, PJ Roufogalis, BD

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Publication Type:: Journal Article
Citation:: Biochimica et Biophysica Acta - Molecular Cell Research, 2007, 1773 (7), pp. 1062 - 1072
Issue Date:: 2007-07-01

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Field	Value	Language
dc.contributor.author	Fu, D	en_US
dc.contributor.author	van Dam, EM	en_US
dc.contributor.author	Brymora, A	en_US
dc.contributor.author	Duggin, IG https://orcid.org/0000-0003-4868-7350	en_US
dc.contributor.author	Robinson, PJ	en_US
dc.contributor.author	Roufogalis, BD	en_US
dc.date.available	2007-03-27	en_US
dc.date.issued	2007-07-01	en_US
dc.identifier.citation	Biochimica et Biophysica Acta - Molecular Cell Research, 2007, 1773 (7), pp. 1062 - 1072	en_US
dc.identifier.issn	0167-4889	en_US
dc.identifier.uri	http://hdl.handle.net/10453/16873
dc.description.abstract	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. © 2007 Elsevier B.V. All rights reserved.	en_US
dc.relation.ispartof	Biochimica et Biophysica Acta - Molecular Cell Research	en_US
dc.relation.isbasedon	10.1016/j.bbamcr.2007.03.023	en_US
dc.subject.mesh	Cell Line	en_US
dc.subject.mesh	Cell Membrane	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Daunorubicin	en_US
dc.subject.mesh	rab5 GTP-Binding Proteins	en_US
dc.subject.mesh	ral GTP-Binding Proteins	en_US
dc.subject.mesh	P-Glycoproteins	en_US
dc.subject.mesh	Recombinant Fusion Proteins	en_US
dc.subject.mesh	Antibiotics, Antineoplastic	en_US
dc.subject.mesh	Drug Resistance, Multiple	en_US
dc.subject.mesh	Biological Transport	en_US
dc.subject.mesh	Mutation	en_US
dc.subject.mesh	ATP Binding Cassette Transporter, Subfamily B	en_US
dc.title	The small GTPases Rab5 and RalA regulate intracellular traffic of P-glycoprotein	en_US
dc.type	Journal Article
utslib.citation.volume	7	en_US
utslib.citation.volume	1773	en_US
utslib.for	0601 Biochemistry and Cell Biology	en_US
utslib.for	06 Biological Sciences	en_US
utslib.for	11 Medical and Health Sciences	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Strength - ithree - Institute of Infection, Immunity and Innovation
utslib.copyright.status	closed_access
pubs.issue	7	en_US
pubs.publication-status	Published	en_US
pubs.volume	1773	en_US

Abstract:

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. © 2007 Elsevier B.V. All rights reserved.

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http://hdl.handle.net/10453/16873