Basal c-Jun NH2-terminal protein kinase activity is essential for survival and proliferation of T-cell acute lymphoblastic leukemia cells
Basal c-Jun NH2-terminal protein kinase activity is essential for survival and proliferation of T-cell acute lymphoblastic leukemia cells
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DOI：
10.1158/1535-7163.mct-09-0408
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发表时间：
2009-12-01
影响因子：
5.7
通讯作者：
Zhang, Jiyan
中科院分区：
文献类型：
--
作者：
Cui, Jian;Wang, Qingyang;Zhang, Jiyan
c-Jun氨基末端蛋白激酶（JNK）的过度激活已被发现在各种恶性淋巴细胞和JNK活性的抑制导致细胞周期阻滞和凋亡。然而，JNK活性在T细胞急性淋巴细胞白血病（T-ALL）细胞的致癌生长中的作用在很大程度上仍然未知。在这里，我们报告说，治疗T-ALL细胞与JNK抑制剂导致细胞周期停滞和凋亡，并增加敏感性Fas介导的凋亡，而弱异位表达的MKK 7-JNK 1融合蛋白，这表明组成型JNK活性，在T-ALL细胞导致细胞周期进程加速和抵抗Fas介导的凋亡。c-Myc和Bcl-2的蛋白水平在JNK抑制剂存在下降低，但在MKK 7-JNK 1存在下增强。针对JNK 1而非JNK 2的小干扰RNA表现出与JNK抑制剂相似的作用。这些发现表明，靶向JNK，特别是JNK 1亚型，可能在T-ALL的治疗中具有一些重要的治疗意义。进一步研究发现，JNK蛋白和JNK活性在TALL细胞中显示异常的亚细胞定位，但没有观察到JNK的过度激活。因此，我们的工作表明，可能有新的机制（S）以外的过度激活的潜在的促肿瘤作用的JNK活性。[Mol Cancer Ther 2009;8（12）：3214-22]
Hyperactivation of c-Jun NH2-terminal protein kinase (JNK) has been found in various malignant lymphocytes and inhibition of JNK activity leads to cell cycle arrest and apoptosis. However, the role of JNK activity in the oncogenic growth of T-cell acute lymphoblastic leukemia (T-ALL) cells remains largely unknown. Here, we report that treatment of T-ALL cells with JNK inhibitors led to cell cycle arrest and apoptosis and increased sensitivity to Fas-mediated apoptosis, whereas weak ectopic expression of MKK7-JNK 1 fusion protein, which shows constitutive JNK activity, in T-ALL cells resulted in accelerated cell cycle progression and resistance to Fas-mediated apoptosis. The protein levels of c-Myc and Bcl-2 were reduced in the presence of JNK inhibitors but were enhanced with MKK7-JNK1. Small interfering RNA against JNK1, but not JNK2, exhibited similar effects to JNK inhibitors. These findings suggest that targeting JNK, especially JNK1 isoform, may have some important therapeutic implications in the treatment of T-ALL. Further exploration revealed that JNK protein and basal JNK activity in TALL cells showed aberrant subcellular localization, but no hyperactivation of JNK was observed. Thus, our work suggests that there might be novel mechanism(s) other than hyperactivation underlying the protumorigenic role of JNK activity. [Mol Cancer Ther 2009;8(12):3214-22]