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Activation of beta-catenin signalling by GSK-3 inhibition increases p-glycoprotein expression in brain endothelial cells.
J Neurochem ; 106(4): 1855-65, 2008 Aug.
Article in En | MEDLINE | ID: mdl-18624906
ABSTRACT
This study investigates involvement of beta-catenin signalling in regulation of p-glycoprotein (p-gp) expression in endothelial cells derived from brain vasculature. Pharmacological interventions that enhance or that block beta-catenin signalling were applied to primary rat brain endothelial cells and to immortalized human brain endothelial cells, hCMEC/D3, nuclear translocation of beta-catenin being determined by immunocytochemistry and by western blot analysis to confirm effectiveness of the manipulations. Using the specific glycogen synthase kinase-3 (GSK-3) inhibitor 6-bromoindirubin-3'-oxime enhanced beta-catenin and increased p-gp expression including activating the MDR1 promoter. These increases were accompanied by increases in p-gp-mediated efflux capability as observed from alterations in intracellular fluorescent calcein accumulation detected by flow cytometry. Similar increases in p-gp expression were noted with other GSK-3 inhibitors, i.e. 1-azakenpaullone or LiCl. Application of Wnt agonist [2-amino-4-(3,4-(methylenedioxy) benzylamino)-6-(3-methoxyphenyl)pyrimidine] also enhanced beta-catenin and increased transcript and protein levels of p-gp. By contrast, down-regulating the pathway using Dickkopf-1 or quercetin decreased p-gp expression. Similar changes were observed with multidrug resistance protein 4 and breast cancer resistance protein, both known to be present at the blood-brain barrier. These results suggest that regulation of p-gp and other multidrug efflux transporters in brain vasculature can be influenced by beta-catenin signalling.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Brain / Signal Transduction / Gene Expression Regulation / ATP Binding Cassette Transporter, Subfamily B, Member 1 / Glycogen Synthase Kinase 3 / Endothelial Cells / Beta Catenin Limits: Animals / Humans / Male Language: En Journal: J Neurochem Year: 2008 Document type: Article Affiliation country: United kingdom Publication country: ENGLAND / ESCOCIA / GB / GREAT BRITAIN / INGLATERRA / REINO UNIDO / SCOTLAND / UK / UNITED KINGDOM

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Brain / Signal Transduction / Gene Expression Regulation / ATP Binding Cassette Transporter, Subfamily B, Member 1 / Glycogen Synthase Kinase 3 / Endothelial Cells / Beta Catenin Limits: Animals / Humans / Male Language: En Journal: J Neurochem Year: 2008 Document type: Article Affiliation country: United kingdom Publication country: ENGLAND / ESCOCIA / GB / GREAT BRITAIN / INGLATERRA / REINO UNIDO / SCOTLAND / UK / UNITED KINGDOM