Li S, Szymborski A, Miron M-J, Marcellus R, Binda O, Lavoie J N, Branton P E
Department of Biochemistry, McGill University, McIntyre Medical Building, Montréal, Québec, Canada.
Oncogene. 2009 Jan 22;28(3):390-400. doi: 10.1038/onc.2008.393. Epub 2008 Oct 27.
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.
人腺病毒E4orf4蛋白单独表达时，可在多种癌细胞中诱导不依赖p53的细胞死亡。我们团队早期的研究表明，尽管在某些情况下细胞死亡可能与凋亡的一些特征相关，但它并不总是受半胱天冬酶抑制剂的影响。因此，E4orf4诱导的细胞死亡不太可能仅通过凋亡发生。在本研究中，以H1299人肺癌细胞为模型系统，我们发现细胞死亡是在未激活任何测试的半胱天冬酶、未积累活性氧或未从线粒体释放细胞色素c的情况下诱导发生的。E4orf4导致细胞形态发生显著变化，包括剧烈的细胞膜起泡、许多细胞出现多核以及细胞体积增大。这些特征大多并非凋亡的典型特征，而是坏死的特征。对细胞周期标志物的流式细胞术分析和蛋白质印迹显示，表达E4orf4的细胞在G(2)/M期停滞，并且还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带有微核的细胞的存在表明，E4orf4似乎通过有丝分裂灾难导致的过程在这些细胞中诱导死亡。
