Journal
FEBS LETTERS
Volume 583, Issue 2, Pages 425-429Publisher
WILEY
DOI: 10.1016/j.febslet.2008.12.041
Keywords
Equilibrative nucleoside transporter; 1-beta-D-Arabinofuranosylcytosine; Drug resistance; Missense mutation; Leukemia cell
Funding
- NIH [RO1-GM069976]
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The genetic basis for the Ara-C resistance of CCRF-CEM Ara-C/8C leukemia cells was investigated. DNA sequencing revealed that these cells expressed an equilibrative nucleoside transporter 1 (ENT1) with a single missense mutation resulting in glycine to arginine replacement (G24R). To test the importance of this residue, additional G24 mutants were created and examined for [3H]-uridine and [3H]-Ara-C uptake. Both a G24E and G24A mutant showed reduced ENT1-dependent activity. An EGFP-tagged G24R ENT1 displayed plasma membrane localization even though it was unable to bind [3H]-NBMPR, an ENT1-specific inhibitor. These results de. ne G24 as critical amino acid for ENT1 nucleoside uptake and suggest that mutations in TM1 may provide a mechanism for Ara-C resistance in CCRF-CEM Ara-C/8C cells. (C) 2008 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved.
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