Peroxisome proliferator-activated receptor gamma-regulated ABCG2 expression confers cytoprotection to human dendritic cells.
ABCG2, a member of the ATP-binding cassette transporters has been identified as a protective pump against endogenous and exogenous toxic agents. ABCG2 was shown to be expressed at high levels in stem cells and variably regulated during cell differentiation. Here we demonstrate that functional ABCG2 is expressed in human monocyte-derived dendritic cells by the activation of a nuclear hormone receptor, PPARgamma. We identified and characterized a 150-base pair long conserved enhancer region, containing three functional PPAR response elements (PPARE), upstream of the human ABCG2 gene. We confirmed the binding of the PPARgamma x RXR heterodimer to this enhancer region, suggesting that PPARgamma directly regulates the transcription of ABCG2. Consistent with these results, elevated expression of ABCG2 mRNA was coupled to enhanced protein production, resulting in increased xenobiotic extrusion capacity via ABCG2 in PPARgamma-activated cells. Furthermore PPARgamma instructed dendritic cells showed increased Hoechst dye extrusion and resistance to mitoxantrone. Collectively, these results uncovered a mechanism by which up-regulation of functional ABCG2 expression can be achieved via exogenous or endogenous activation of the lipid-activated transcription factor, PPARgamma. The increased expression of the promiscuous ABCG2 transporter can significantly modify the xenobiotic and drug resistance of human myeloid dendritic cells.
Szatmari
Istvan
I
Department of Biochemistry and Molecular Biology, Research Center for Molecular Medicine, University of Debrecen, Hungary.
Vámosi
György
G
Brazda
Peter
P
Balint
Balint L
BL
Benko
Szilvia
S
Széles
Lajos
L
Jeney
Viktoria
V
Ozvegy-Laczka
Csilla
C
Szántó
Attila
A
Barta
Endre
E
Balla
József
J
Sarkadi
Balazs
B
Nagy
Laszlo
L
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001483:Base Sequence; D002417:Cattle; D019610:Cytoprotection / Q000502:physiology*; D003713:Dendritic Cells / Q000166:cytology* / Q000378:metabolism*; D004285:Dogs; D019008:Drug Resistance, Neoplasm; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D047495:PPAR gamma / Q000819:agonists / Q000502:physiology*; D010641:Phenotype; D015854:Up-Regulation / Q000502:physiology; D015262:Xenobiotics / Q000378:metabolism
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D009363:Neoplasm Proteins; D047495:PPAR gamma; D015262:Xenobiotics