Cloning and Functional Analysis of the Rhesus Macaque ABCG2 Gene

Ueda, Takahiro; Brenner, Sebastian; Malech, Harry L.; Langemeijer, Saskia; Kirby, Martha; Phang, Oswald; Krouse, Allen E.; Donahue, Robert E.; Kang, Elizabeth M.; Tisdale, John F.

doi:10.1074/jbc.m409796200

Cited by 13 publications

(1 citation statement)

References 38 publications

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“…In addition to its role in drug disposition, ABCG2 has become a popular marker for identifying progenitor cells in a wide array of tissues, although its function in these cells is unclear (31)(32)(33)(34)(35). As an ABC superfamily member, ABCG2 is similar to other MRPs in its ability to protect cells against chemical insults; but it is unlike other MRPs in that ABCG2 is a member of the half-transporter G (WHITE) subfamily.…”

Section: Discussionmentioning

confidence: 99%

Glutathione Transport Is a Unique Function of the ATP-binding Cassette Protein ABCG2

Brechbuhl

Gould

Kachadourian

et al. 2010

Journal of Biological Chemistry

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Glutathione (GSH) transport is vital for maintenance of intracellular and extracellular redox balance. Only a few human proteins have been identified as transporters of GSH, glutathione disulfide (GSSG) and/or GSH conjugates (GS-X). Human epithelial MDA1586, A549, H1975, H460, HN4, and H157 cell lines were exposed to 2,5-dihydroxychalcone, which induces a GSH efflux response. A real-time gene superarray for 84 proteins found in families that have a known role in GSH, GSSG, and/or GS-X transport was employed to help identify potential GSH transporters. ABCG2 was identified as the only gene in the array that closely corresponded with the magnitude of 2,5-dihydroxychalcone (2,5-DHC)-induced GSH efflux. The role of human ABCG2 as a novel GSH transporter was verified in a Saccharomyces cerevisiae galactose-inducible gene expression system. Yeast expressing human ABCG2 had 2.5-fold more extracellular GSH compared with those not expressing ABCG2. GSH efflux in ABCG2-expressing yeast was abolished by the ABCG2 substrate methotrexate (10 M), indicating competitive inhibition. In contrast, 2,5-DHC treatment of ABCG2-expressing yeast increased extracellular GSH levels in a dose-dependent manner with a maximum 3.5-fold increase in GSH after 24 h. In addition, suppression of ABCG2 with short hairpin RNA or ABCG2 overexpression in human epithelial cells decreased or increased extracellular GSH levels, respectively. Our data indicate that ABCG2 is a novel GSH transporter.Glutathione (GSH) is a tripeptide (␥-glutamyl-cysteinyl-glycine) that is maintained at millimolar concentrations within the cell. It is important in many signaling processes, including cell proliferation, post-translational modification of proteins, immune responses, and apoptosis (1, 2). The importance of GSH in normal cell function as well as its role in disease states such as cancer, cystic fibrosis, Parkinson disease, AIDS, liver dysfunction, and a host of other maladies has been well documented (3-8). For the purpose of detoxification and to respond to extracellular oxidative stress, cells express membrane proteins capable of transporting GSH, glutathione disulfide (GSSG), and GSH conjugates (GS-X).2 Currently, there are only a handful of proteins identified as capable of transporting GSH across membranes.The first human protein identified as a GS-X and/or GSSG transporter was the ATP-binding cassette (ABC) protein ABCC1, first called the GSH S-conjugate pump and later identified as the multidrug resistance protein MRP1 (9 -11). Since the discovery of ABCC1 as a GSH transporter, five other ABC family members have been shown to transport GSH and/or GS-X, including ABCC2, ABCC3, ABCC4, ABCC5, and ABCC7 (12-17). GSH transport has also been linked to the organic anion transporting polypeptide protein family, a subfamily of the solute carrying (SLC) protein superfamily. The SLC superfamily also contains mitochondria-specific membrane proteins (SLC25) capable of transporting GSH (18).Numerous compounds stimulate GSH, GSSG, and GS-X efflux through the ABC protei...

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Section: Discussionmentioning

confidence: 99%

Glutathione Transport Is a Unique Function of the ATP-binding Cassette Protein ABCG2

Brechbuhl

Gould

Kachadourian

et al. 2010

Journal of Biological Chemistry

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Side populations from cervical-cancer-derived cell lines have stem-cell-like properties

et al. 2014

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The target cells for the transforming mutations caused by high-risk human papillomavirus (HPV) infection could be the stem cells of the uterine cervical epithelium, generating particular cancer stem cells (CSCs). The aim of this study was to identify and characterize the CSCs from cervical-cancer-derived cell lines. The ability of SiHa, CaLo, and C-33A cell lines to efflux Hoechst 33342 was evaluated by flow cytometry and cells from the corresponding side populations (SPs) and nonside populations (NSPs) were analyzed for their cell-cycle status (pyronin Y) and their mRNA levels of ABC transporter family members (with qPCR). Specific markers (α6-integrin(bri)/CD71(dim), CK17) of normal epithelial stem cells were evaluated by flow cytometry. The biological properties of these cells were analyzed, including their colony heterogeneity, repopulation, and anchorage-independent colony formation. We identified SPs (around 3 %) in the SiHa and CaLo cell lines, more than 70 % of which were in G0 phase and strongly expressed ABC transporters (predominantly ABCG2 and ABCB1). The SP from CaLo cells showed an α6-integrin(bri)/CD(dim) pattern, whereas the SP from the SiHa cells showed an α6-integrin(-)/CD(dim) pattern. Recultured cells from the SPs of both cell lines generated both SPs and NSPs, and had higher clonogenic potential to form mainly holoclones and greater colony-forming efficiency under anchorage-independent growth conditions than the cells from the NSPs or total cell populations. Interestingly, we identified no SP in the HPV-uninfected C-33A cell line, and it did not express ABCG2 or other members of the ABC transporters (ABCB1, ABCC1, or ABCA3).

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BCRP/ABCG2 in the Placenta: Expression, Function and Regulation

Mao

2008

Pharm Res

127

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Abstract. Knowledge concerning transport of maternally administered drugs across the placental barrier is essential for determining potential toxicity of drugs to the fetus and the value of drug therapy during pregnancy. An important determinant for fetal drug exposure is the expression of efflux transporters in the placenta. Among human tissues, the ATP-binding cassette efflux transporter BCRP (gene symbol ABCG2) is most abundantly expressed in the apical membrane of placental syncytiotrophoblasts. Although the precise physiological role of BCRP in the placenta is still unclear, existing data strongly suggest that BCRP plays an important role in protecting the fetus against the potential toxicity of drugs, xenobiotics, and metabolites by expelling them across the placental barrier. In this review, we summarize the current knowledge with respect to the expression, function, and polymorphisms of BCRP, as well as transcriptional and posttranscriptional regulation of the transporter in the placenta. Finally, clinical significance of BCRP in the placenta for drug therapy in pregnant women is discussed.

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Cloning and Functional Analysis of the Rhesus Macaque ABCG2 Gene

Cited by 13 publications

References 38 publications

Glutathione Transport Is a Unique Function of the ATP-binding Cassette Protein ABCG2

Glutathione Transport Is a Unique Function of the ATP-binding Cassette Protein ABCG2

Side populations from cervical-cancer-derived cell lines have stem-cell-like properties

BCRP/ABCG2 in the Placenta: Expression, Function and Regulation

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