NPM-ALK oncogenic kinase promotes cell-cycle progression through activation of JNK/cJun signaling in anaplastic large-cell lymphoma
NPM-ALK oncogenic kinase promotes cell-cycle progression through activation of JNK/cJun signaling in anaplastic large-cell lymphoma
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DOI：
10.1182/blood-2006-11-059451
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发表时间：
2007-09-01
期刊：
影响因子：
20.3
通讯作者：
Rassiclakis, George Z.
中科院分区：
文献类型：
--
作者：
Leventaki, Vasiliki;Drakos, Elias;Rassiclakis, George Z.
间变性大细胞淋巴瘤(ALCL)常携带t(2；5)(p23；q35)，导致核磷蛋白间变性淋巴瘤激酶(NPM-ALK)异常表达。我们发现，在293T和Jurkat细胞中，强制表达活性的NPM-ALK，而不是激酶死亡的突变体NPM-ALK(210K和GT；R)，诱导了JNK和cJun的磷酸化，这与AP-1转录活性的急剧增加有关。相反，抑制NPM-ALK(+)ALCL细胞的ALK活性可导致JNK和cJun的浓度依赖性磷酸化，并减少AP-1DNA结合。此外，JNK在物理上与NPM-ALK结合，并在培养和原代NPM-ALK(+)ALCL细胞中高度激活。在NPM-ALK+ALCL细胞中，cJun的磷酸化是由JNKs介导的，通过siRNA选择性地下调JNK1和JNK2基因。用SP600125抑制JNK活性可降低cJun磷酸化和AP-1转录活性，并以剂量依赖方式抑制细胞增殖和G2/M期停滞。通过siRNA沉默cJun基因，导致细胞周期中p21表达上调、细胞周期蛋白D3和细胞周期蛋白A表达下调，导致S期细胞周期比例下降。综上所述，这些发现揭示了NPM-ALK的一种新功能，即JNK和cJun的磷酸化和激活，这可能与细胞周期进程失控和肿瘤的发生有关。
Anaplastic large-cell lymphoma (ALCL) frequently carries the t(2;5)(p23;q35), resulting in aberrant expression of nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). We show that in 293T and Jurkat cells, forced expression of active NPM-ALK, but not kinase-dead mutant NPM-ALK (210K > R), induced JNK and cJun phosphorylation, and this was linked to a dramatic increase in AP-1 transcriptional activity. Conversely, inhibition of ALK activity in NPM-ALK(+) ALCL cells resulted in a concentration-dependent phosphorylation of JNK and cJun and decreased AP-1 DNA-binding. In addition, JNK physically binds NPM-ALK and is highly activated in cultured and primary NPM-ALK(+) ALCL cells. cJun phosphorylation in NPM-ALK+ ALCL cells is mediated by JNKs, as shown by selective knocking down of JNK1 and JNK2 genes using siRNA. Inhibition of JNK activity using SP600125 decreased cJun phosphorylation and AP-1 transcriptional activity and this was associated with decreased cell proliferation and G2/M cell-cycle arrest in a dose-dependent manner. Silencing of the cJun gene by siRNA led to a decreased S-phase cell-cycle fraction associated with upregulation of p21 and down-regulation of cyclin D3 and cyclin A. Taken together, these findings reveal a novel function of NPM-ALK, phosphorylation and activation of JNK and cJun, which may contribute to uncontrolled cell-cycle progression and oncogenesis.