RGD Reference Report - Modulation of P-glycoprotein function by sphingosine kinase-1 in brain endothelial cells. - Rat Genome Database

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Modulation of P-glycoprotein function by sphingosine kinase-1 in brain endothelial cells.

Authors: Pilorget, A  Demeule, M  Barakat, S  Marvaldi, J  Luis, J  Beliveau, R 
Citation: Pilorget A, etal., J Neurochem. 2007 Mar;100(5):1203-10.
RGD ID: 2311379
Pubmed: PMID:17316399   (View Abstract at PubMed)
DOI: DOI:10.1111/j.1471-4159.2006.04295.x   (Journal Full-text)

P-glycoprotein (P-gp), an ABC-transporter highly expressed in brain capillaries, protects the brain by extruding xenobiotics. However, its overexpression has also been associated with the multidrug resistance phenotype in tumors. Here, we have investigated the regulation of P-gp transport activity by sphingosine kinase 1 (SphK-1) in brain endothelial cells. We first demonstrated that SphK-1 is overexpressed in endothelial cells (EC) isolated from rat brain tumors compared with EC from normal brain. We also provide evidence that the overexpression of SphK-1 in the cerebral EC line RBE4 leads to the up-regulation of P-gp, both at the gene and protein levels, and that this modulation depends on the catalytic activity of SphK-1. Moreover, we determined the effect of sphingosine-1-phosphate (S1P), the product of SphK-1, on P-gp function. S1P strongly stimulates P-gp transport activity, without modulating its expression. Finally, we found that the S1P-mediated stimulation of P-gp activity is mediated by S1P-1 and S1P-3 receptors at the RBE4 cell surface. Altogether, these results indicate that SphK-1 and its product S1P are involved in the control of P-gp activity in RBE4 cells. Since SphK-1 is overexpressed in EC from brain tumors, these data also suggest that this kinase and its product could contribute to the acquisition and the maintenance of the multidrug resistance phenotype in brain tumor-derived endothelial cells.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
high grade glioma  ISOSphk1 (Rattus norvegicus)2311379; 2311379protein:increased expression:endothelial cell (rat)RGD 
high grade glioma  IEP 2311379protein:increased expression:endothelial cell (rat)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Sphk1  (sphingosine kinase 1)

Genes (Mus musculus)
Sphk1  (sphingosine kinase 1)

Genes (Homo sapiens)
SPHK1  (sphingosine kinase 1)


Additional Information