Identification of a novel point mutation in ENT1 that confers resistance to Ara-C in human T cell leukemia CCRF-CEM cells.
Identification of a novel point mutation in ENT1 that confers resistance to Ara-C in human T cell leukemia CCRF-CEM cells.
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DOI：
10.1016/j.febslet.2008.12.041
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发表时间：
2009-01-22
期刊：
影响因子：
3.5
通讯作者：
Graves LM
中科院分区：
文献类型：
--
作者：
Zimmerman EI;Huang M;Leisewitz AV;Wang Y;Yang J;Graves LM
本文探讨了CCRF-CEM Ara-C/8 C白血病细胞对Ara-C耐药的遗传学基础。DNA测序显示，这些细胞表达平衡核苷转运蛋白1（ENT 1）与一个单一的错义突变，导致甘氨酸精氨酸取代（G24 R）。为了测试该残基的重要性，产生了另外的G24突变体并检查了[3 H]-尿苷和[3 H]-Ara-C摄取。G24 E和G24 A突变体均显示降低的ENT 1依赖性活性。EGFP标记的G24 R ENT 1显示质膜定位，即使它不能结合[3 H]-NBMPR，ENT 1特异性抑制剂。这些结果将G24定义为ENT 1核苷摄取的关键氨基酸，并表明TM 1中的突变可能提供CCRF-CEM Ara-C/8 C细胞中Ara-C抗性的机制。
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 define 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.
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