The adenovirus E4orf4 protein induces growth arrest and mitotic catastrophe in H1299 human lung carcinoma cells
The adenovirus E4orf4 protein induces growth arrest and mitotic catastrophe in H1299 human lung carcinoma cells
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DOI：
10.1038/onc.2008.393
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发表时间：
2009-01-22
期刊：
影响因子：
8
通讯作者：
Branton, P. E.
中科院分区：
文献类型：
--
作者：
Li, S.;Szymborski, A.;Branton, P. E.
人腺病毒E4orf4蛋白单独表达时，可在多种癌细胞中诱导非p53依赖的死亡。我们小组的早期研究表明，尽管在某些情况下，细胞死亡可以与某些细胞凋亡的特征有关，但它并不总是受到caspase抑制剂的影响。因此，E4orf4诱导的细胞死亡不太可能仅通过细胞凋亡发生。在以H1299人肺癌细胞为模型系统的研究中，我们发现，在没有被测试的任何半胱氨酸酶的激活，没有活性氧积累，或者没有细胞色素c从线粒体释放的情况下，死亡是被诱导的。E4orf4引起细胞形态的实质性变化，包括强烈的膜气泡，许多细胞有多个核，细胞体积增加。这些特征大多不是典型的细胞凋亡，但它们是坏死性的。流式细胞仪分析和免疫印迹分析显示，E4orf4表达的细胞被滞留在G(2)/M期，并积累了高水平的细胞周期蛋白E。大量四倍体和多倍体细胞以及一些微核细胞的存在表明，E4orf4可能通过有丝分裂突变导致这些细胞死亡。
The human adenovirus E4orf4 protein, when expressed alone, induces p53-independent death in a wide range of cancer cells. Earlier studies by our groups suggested that although in some cases cell death can be associated with some hallmarks of apoptosis, it is not always affected by caspase inhibitors. Thus it is unlikely that E4orf4-induced cell death occurs uniquely through apoptosis. In the present studies using H1299 human lung carcinoma cells as a model system we found that death is induced in the absence of activation of any of the caspases tested, accumulation of reactive oxygen species, or release of cytochrome c from mitochondria. E4orf4 caused a substantial change in cell morphology, including vigorous membrane blebbing, multiple nuclei in many cells and increased cell volume. Most of these characteristics are not typical of apoptosis, but they are of necrosis. FACS analysis and western blotting for cell cycle markers showed that E4orf4-expressing cells became arrested in G(2)/M and also accumulated high levels of cyclin E. The presence of significant numbers of tetraploid and polyploid cells and some cells with micronuclei suggested that E4orf4 appears to induce death in these cells through a process resulting from mitotic catastrophe.