Novel role of c-jun N-terminal kinase in regulating the initiation of cap-dependent translation.
Novel role of c-jun N-terminal kinase in regulating the initiation of cap-dependent translation.
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DOI：
10.3892/ijo.2011.1252
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发表时间：
2012-02
影响因子：
5.2
通讯作者：
Kratzke RA
中科院分区：
文献类型：
--
作者：
Patel MR;Sadiq AA;Jay-Dixon J;Jirakulaporn T;Jacobson BA;Farassati F;Bitterman PB;Kratzke RA
通过5' mRNA帽启动蛋白质翻译是细胞生长和增殖中严格调控的步骤。帽依赖性翻译的异常激活是包括非小细胞肺癌在内的许多癌症的标志。导致翻译起始的典型信号传导机制包括Akt/mTOR途径响应于营养物和生长因子的存在而活化。我们以前已经观察到，c-jun N-末端激酶（JNK）的抑制导致间皮瘤细胞中帽依赖性翻译的失活。由于JNK参与非小细胞肺癌（NSCLC）的发生，我们假设JNK也可能参与激活NSCLC细胞中的帽依赖性翻译，并可能代表调节翻译的替代途径。在一系列NSCLC细胞系中，使用SP 600125抑制JNK导致4 E-BP 1磷酸化的抑制和帽依赖性翻译复合物eIF 4F的形成减少。此外，我们表明JNK介导的翻译抑制是独立的mTOR。我们的数据提供的证据表明，JNK参与了翻译的调节，并有潜力作为NSCLC的治疗靶点。
Initiation of protein translation by the 5' mRNA cap is a tightly regulated step in cell growth and proliferation. Aberrant activation of cap-dependent translation is a hallmark of many cancers including non-small cell lung cancer. The canonical signaling mechanisms leading to translation initiation include activation of the Akt/mTOR pathway in response to the presence of nutrients and growth factors. We have previously observed that inhibition of c-jun N-terminal kinase (JNK) leads to inactivation of cap-dependent translation in mesothelioma cells. Since JNK is involved in the genesis of non-small cell lung cancer (NSCLC), we hypothesized that JNK could also be involved in activating cap-dependent translation in NSCLC cells and could represent an alternative pathway regulating translation. In a series of NSCLC cell lines, inhibition of JNK using SP600125 resulted in inhibition of 4E-BP1 phosphorylation and a decrease in formation of the cap-dependent translation complex, eIF4F. Furthermore, we show that JNK-mediated inhibition of translation is independent of mTOR. Our data provide evidence that JNK is involved in the regulation of translation and has potential as a therapeutic target in NSCLC.
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