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Modulation of p‐glycoprotein function by caveolin‐1 phosphorylation
Author(s) -
Barakat Stéphane,
Demeule Michel,
Pilorget Anthony,
Régina Anthony,
Gingras Denis,
Baggetto Loris G.,
Béliveau Richard
Publication year - 2007
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2006.04410.x
Subject(s) - caveolin 1 , phosphorylation , transfection , immunoprecipitation , p glycoprotein , biology , caveolae , vinblastine , microbiology and biotechnology , atp binding cassette transporter , endothelial stem cell , tyrosine phosphorylation , cell culture , signal transduction , transporter , biochemistry , in vitro , multiple drug resistance , gene , antibiotics , chemotherapy , genetics
p‐glycoprotein (p‐gp) is an ATP‐binding cassette transporter and its overexpression is responsible for the acquisition of the multidrug resistance phenotype in human tumors. p‐gp is localized at the blood–brain barrier and is involved in brain cytoprotection. Our previous work used immunoprecipitation to show that caveolin‐1 can interact with p‐gp. In this study, we provide evidence that caveolin‐1 regulates p‐gp transport activity in a rat brain endothelial cell line (RBE4). Down‐regulation of caveolin‐1 by siRNA reduced the interaction between p‐gp and caveolin‐1, followed by a decrease in [ 3 H]‐Taxol and [ 3 H]‐Vinblastine accumulation in RBE4 cells. The latter result showed that down‐regulation of caveolin‐1 enhanced p‐gp transport activity. RBE4 cells were also transfected with Sarcoma in order to modulate caveolin‐1 phosphorylation. Overexpression of Sarcoma, a protein tyrosine kinase, stimulated caveolin‐1 phosphorylation and increased both [ 3 H]‐Taxol and [ 3 H]‐Vinblastine accumulation as well as Hoechst 33342 accumulation. Transfection of caveolin‐1 inhibits p‐gp transport activity. Conversely, transfection of the mutant cavY14F decreased the p‐gp/caveolin‐1 interaction and reduced accumulation of the two p‐gp substrates. Thus, our data show that caveolin‐1 regulates p‐gp function through the phosphorylation state of caveolin‐1 in endothelial cells from the blood–brain barrier.