Defective translational control facilitates vesicular stomatitis virus oncolysis
Defective translational control facilitates vesicular stomatitis virus oncolysis
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DOI：
10.1016/s1535-6108(03)00330-1
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发表时间：
2004-01-01
期刊：
影响因子：
50.3
通讯作者：
Barber, GN
中科院分区：
文献类型：
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作者：
Balachandran, S;Barber, GN
水泡性口炎病毒（VSV）具有强大的抗肿瘤活性，但其溶瘤特性的分子机制仍有待充分阐明。在这里，我们证明，正常耐药鼠胚胎成纤维细胞被赋予高度允许VSV复制后，细胞转化，进展，似乎妥协干扰素（IFN）的抗病毒作用。随后的研究揭示了正常的dsRNA依赖性蛋白激酶（PKR）激活和真核起始因子2（eIF2）α的磷酸化。然而，eIF2B介导的eIF2下游的鸟嘌呤核苷酸交换活性在转化细胞中经常异常，中和eIF2 α磷酸化并允许VSV mRNA翻译。因此，翻译调控的缺陷可以与受损的IFN信号传导合作，以促进VSV复制，并可能代表肿瘤发生的共同标志。
Vesicular stomatitis virus (VSV) exerts potent antitumor activity, although the molecular mechanisms underlying its oncolytic properties remain to be fully clarified. Here, we demonstrate that normally resistant murine embryonic fibroblasts are rendered highly permissive to VSV replication following cellular transformation, a progression that appears to compromise the antiviral effects of interferon (IFN). Subsequent studies revealed normal dsRNA-dependent protein kinase (PKR) activation and phosphorylation of eukaryotic initiation factor 2 (eIF2)alpha. Nevertheless, eIF2B-mediated guanine nucleotide exchange activity downstream of eIF2 was frequently aberrant in transformed cells, neutralizing eIF2alpha phosphorylation and permitting VSV mRNA translation. Thus, defects in translational regulation can cooperate with impaired IFN signaling to facilitate VSV replication, and may represent a common hallmark of tumorigenesis.