PEA-15 is inhibited by adenovirus E1A and plays a role in ERK nuclear export and Ras-induced senescence
PEA-15 is inhibited by adenovirus E1A and plays a role in ERK nuclear export and Ras-induced senescence
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DOI：
10.1074/jbc.m403893200
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发表时间：
2004-11-05
影响因子：
4.8
通讯作者：
Ferbeyre, G
中科院分区：
文献类型：
--
作者：
Gaumont-Leclerc, MF;Mukhopadhyay, UK;Ferbeyre, G
致癌ras激活多种信号通路以促进肿瘤细胞的增殖。ERK 1/2丝裂原活化蛋白激酶途径是ras转化作用所必需的，其活化通常足以传递促有丝分裂刺激。然而，在某些情况下，致癌ras触发细胞周期的永久性停滞与细胞衰老的功能。Ras/ERK 1/2通路如何激活不同的细胞程序还不清楚。在这里，我们表明，ERK 1/2主要定位在细胞质中ras诱导的衰老。这种细胞质定位似乎依赖于一个活跃的核输出机制，并可以被拯救的病毒癌蛋白E1 A。与此假设一致，我们发现E1 A显著下调ERK 1/2核输出因子PEA-15的表达。此外，针对PEA-15的RNA干扰恢复了表达Ras的原代小鼠胚胎成纤维细胞中磷酸化ERK 1/2的核定位，并刺激其逃避衰老。由于衰老阻止致癌ras的转化作用，我们的研究结果表明PEA-15的肿瘤抑制功能，通过控制磷酸化ERK 1/2的定位。
Oncogenic ras activates multiple signaling pathways to enforce cell proliferation in tumor cells. The ERK1/2 mitogen-activated protein kinase pathway is required for the transforming effects of ras, and its activation is often sufficient to convey mitogenic stimulation. However, in some settings oncogenic ras triggers a permanent cell cycle arrest with features of cellular senescence. How the Ras/ERK1/2 pathway activates different cellular programs is not well understood. Here we show that ERK1/2 localize predominantly in the cytoplasm during ras-induced senescence. This cytoplasmic localization seems to be dependent on an active nuclear export mechanism and can be rescued by the viral oncoprotein E1A. Consistent with this hypothesis, we showed that E1A dramatically down-regulated the expression of the ERK1/2 nuclear export factor PEA-15. Also, RNA interference against PEA-15 restored the nuclear localization of phospho-ERK1/2 in Ras-expressing primary murine embryo fibroblasts and stimulated their escape from senescence. Because senescence prevents the transforming effect of oncogenic ras, our results suggest a tumor suppressor function for PEA-15 that operates by means of controlling the localization of phospho-ERK1/2.