Nuclear trafficking of EGFR by Vps34 represses Arf expression to promote lung tumor cell survival
Nuclear trafficking of EGFR by Vps34 represses Arf expression to promote lung tumor cell survival
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DOI：
10.1038/onc.2015.480
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发表时间：
2016-07-28
期刊：
影响因子：
8
通讯作者：
Gazzeri, S.
中科院分区：
文献类型：
--
作者：
Dayde, D.;Guerard, M.;Gazzeri, S.
表皮生长因子受体（EGFR）是一种细胞表面受体，在细胞增殖和存活中具有重要作用，EGFR的过表达是人类癌症的共同特征。在非小细胞肺癌（NSCLC）中，也描述了EGFR的激活突变。我们最近发现突变型EGFR-L 858 R抑制p14 ARF肿瘤抑制蛋白的表达，以促进细胞存活。在这项研究中，我们确定了EGFR控制Arf表达的分子基础。使用各种肺肿瘤模型，我们发现EGF刺激通过涉及EGFR到Arf启动子的核转运和募集的机制抑制Arf转录。我们揭示了囊泡运输蛋白Vps 34作为EGFR核运输的介体，并表明其中和作用可防止EGFR在配体激活后积聚到Arf启动子。最后，在携带突变型EGFR-L 858 R的肺肿瘤细胞中，我们证明了使用小干扰RNA抑制Vps 34抑制细胞核EGFR定位并恢复Arf表达，从而导致细胞凋亡。这些发现确定了Arf肿瘤抑制因子作为核EGFR的新的转录靶点，并强调了Vps 34作为核EGFR/Arf存活途径的重要调节因子。总的来说，它们为NSCLC患者中EGFR的核表达与总生存率之间的负相关性提供了机制解释。
Epidermal growth factor receptor (EGFR) is a cell surface receptor that has an essential role in cell proliferation and survival, and overexpression of EGFR is a common feature of human cancers. In Non-small-cell lung cancer (NSCLC), activating mutations of EGFR have also been described. We recently showed that mutant EGFR-L858R inhibits the expression of the p14ARF tumor-suppressor protein to promote cell survival. In this study, we defined the molecular bases by which EGFR controls Arf expression. Using various lung tumor models, we showed that EGF stimulation inhibits Arf transcription by a mechanism involving the nuclear transport and recruitment of EGFR to the Arf promoter. We unraveled the vesicular trafficking protein Vps34 as a mediator of EGFR nuclear trafficking and showed that its neutralization prevents the accumulation of EGFR to the Arf promoter in response to ligand activation. Finally, in lung tumor cells that carry mutant EGFR-L858R, we demonstrated that inhibition of Vps34 using small interfering RNA restrains nuclear EGFR location and restores Arf expression leading to apoptosis. These findings identify the Arf tumor suppressor as a new transcriptional target of nuclear EGFR and highlight Vps34 as an important regulator of the nuclear EGFR/Arf survival pathway. As a whole, they provide a mechanistic explanation to the inverse correlation between nuclear expression of EGFR and overall survival in NSCLC patients.