mTOR regulates proteasomal degradation and Dp1/E2F1- mediated transcription of KPNA2 in lung cancer cells.
mTOR regulates proteasomal degradation and Dp1/E2F1- mediated transcription of KPNA2 in lung cancer cells.
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DOI：
10.18632/oncotarget.8170
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发表时间：
2016-05-03
期刊：
影响因子：
--
通讯作者：
Yu CJ
中科院分区：
文献类型：
--
作者：
Wang CI;Chen YY;Wang CL;Yu JS;Chang YS;Yu CJ
核仁组成蛋白亚基α2(KPNA2)在多种人类肿瘤中过表达，与肿瘤的侵袭性和患者的不良预后有关。然而，KPNA2在癌症中的表达调控仍不清楚。在此，我们应用表皮生长因子(EGF)和五种表皮生长因子受体(EGFR)相关的激酶抑制剂来研究EGFR信号在非小细胞肺癌(NSCLC)细胞KPNA2表达中的作用。我们发现，在NSCLC细胞中，EGFR信号，特别是哺乳动物雷帕霉素靶标(MTOR)活性与KPNA2蛋白水平呈正相关。MTOR抑制剂和mTOR基因敲除降低了NSCLC和乳腺癌细胞中KPNA2的蛋白和mRNA水平。具体地说，雷帕霉素诱导蛋白酶体介导的KPNA2蛋白降解，并通过降低体内DP1/E2F1水平来减弱KPNA2的转录激活。免疫沉淀分析进一步表明KPNA2与磷酸化mTOR/mTOR物理结合，这种结合可被雷帕霉素处理所消除。总体而言，我们的结果首次表明KPNA2在转录和翻译后受到mTOR途径的调节，并为NSCLC的靶向治疗提供了新的见解。
Karyopherin subunit alpha-2 (KPNA2) is overexpressed in various human cancers and is associated with cancer invasiveness and poor prognosis in patient. Nevertheless, the regulation of KPNA2 expression in cancers remains unclear. We herein applied epidermal growth factor (EGF) and five EGF receptor (EGFR)-related kinase inhibitors to investigate the role of EGFR signaling in KPNA2 expression in non-small cell lung cancer (NSCLC) cells. We found that EGFR signaling, particularly the mammalian target of rapamycin (mTOR) activity was positively correlated with KPNA2 protein levels in NSCLC cells. The mTOR inhibitors and mTOR knockdown reduced the protein and mRNA levels of KPNA2 in NSCLC and breast cancer cells. Specifically, rapamycin treatment induced proteasome-mediated KPNA2 protein decay and attenuated the transcriptional activation of KPNA2 by decreasing Dp1/E2F1 level in vivo. Immunoprecipitation assay further revealed that KPNA2 physically associated with the phospho-mTOR/mTOR and this association was abolished by rapamycin treatment. Collectively, our results show for the first time that KPNA2 is transcriptionally and post-translationally regulated by the mTOR pathway and provide new insights into targeted therapy for NSCLC.
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DOI：
10.1073/pnas.92.5.1769
发表时间：
1995-02-28
影响因子：
11.1
作者：
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影响因子：
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影响因子：
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作者：
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