Inhibition of nucleoside transport by p38 MAPK inhibitors
Inhibition of nucleoside transport by p38 MAPK inhibitors
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DOI：
10.1074/jbc.c200321200
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发表时间：
2002-08-09
影响因子：
4.8
通讯作者：
Graves, LM
中科院分区：
文献类型：
--
作者：
Huang, M;Wang, YH;Graves, LM
在研究p38 MAPK调节红白血病K562细胞阿糖胞苷（Ara C）依赖性分化的能力时，我们观察到的效果表明，咪唑啉类p38 MAPK抑制剂阻止核苷转运。用SB 203580、SB 203580-iodo或SB 202474（不抑制p38 MAPK活性的SB 203580类似物）孵育K562细胞，抑制[H-3]Ara C或[H-3]尿苷的摄取和K562细胞的分化。与这些化合物对硝基苄基硫代肌苷（NBMPR）敏感的平衡型核苷转运蛋白（ENT 1）的作用一致，与SB 203580或SB 203580-碘孵育消除了[H-3]NBMPR与K562细胞或从人红细胞分离的膜的结合。此外，使用尿苷依赖性细胞类型（G9 c），我们观察到SB 203580或SB 203580-iodo有效地抑制了体内嘧啶核苷酸的补救合成。因此，这些研究表明，NBMPR敏感的平衡型核苷转运蛋白是p38 MAPK抑制剂在通常用于抑制蛋白激酶的浓度下的新的和意想不到的靶标。
While investigating the ability of p38 MAPK to regulate cytarabine (Ara C)-dependent differentiation of erythroleukemia K562 cells, we observed effects that indicated that the imidazoline class of p38 MAPK inhibitors prevented nucleoside transport. Incubation of K562 cells with SB203580, SB203580-iodo, or SB202474, an analogue of SB203580 that does not inhibit p38 MAPK activity, inhibited the uptake of [H-3]Ara C or [H-3]uridine and the differentiation of K562 cells. Consistent with the effects of these compounds on the nitrobenzylthioinosine (NBMPR)-sensitive equilibrative nucleoside transporter (ENT1), incubation with SB203580 or SB203580-iodo eliminated the binding of [H-3]NBMPR to K562 cells or membranes isolated from human erythrocytes. Furthermore, using a uridine-dependent cell type (G9c), we observed that SB203580 or SB203580-iodo efficiently inhibited the salvage synthesis of pyrimidine nucleotides in vivo. Thus these studies demonstrate that the NBMPR-sensitive equilibrative nucleoside transporters are novel and unexpected targets for the p38 MAPK inhibitors at concentrations typically used to inhibit protein kinases.