Oncogenes in Ras signalling pathway dictate host-cell permissiveness to herpes simplex virus 1
Oncogenes in Ras signalling pathway dictate host-cell permissiveness to herpes simplex virus 1
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DOI：
10.1038/35087061
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发表时间：
2001-08-01
影响因子：
21.3
通讯作者：
Lee, PWK
中科院分区：
文献类型：
--
作者：
Farassati, F;Yang, AD;Lee, PWK
单纯疱疹病毒（HSV）作为人类病原体的重要性和使用HSV-1的突变衍生物作为潜在的抗癌治疗剂的新兴前景使得有必要对宿主细胞对HSV的容许性的分子基础进行彻底的调查。在这里，我们表明，NIH-3 T3细胞转化的癌基因v-erbB，激活的SOS或激活的ras成为显着更宽容的HSV-1。Ras信号通路的抑制剂，如法尼基转移酶抑制剂1和PD 98069，有效地抑制HSV-1感染的ras转化细胞。转化细胞的增强的容许性与抑制病毒诱导的双链RNA活化蛋白激酶（PKR）的活化（磷酸化）有关，从而允许病毒转录物在这些细胞中翻译。还发现HSV-1衍生的溶瘤突变体R3616优先感染转化细胞和PKR-/-（但不感染PKR+/+）小鼠胚胎成纤维细胞。这些观察结果表明，HSV-1特异性靶向具有激活的Ras信号传导途径的细胞，并且在癌症治疗中使用工程HSV、开发抗HSV感染的策略以及HSV在人类癌症中的有争议的作用方面具有重要的分支。
The importance of herpes simplex viruses (HSV) as human pathogens and the emerging prospect of using mutant derivatives of HSV-1 as potential anti-cancer therapeutics have necessitated a thorough investigation into the molecular basis of host-cell permissiveness to HSV. Here we show that NIH-3T3 cells transformed with the oncogenes v-erbB, activated sos or activated ras become significantly more permissive to HSV-1. Inhibitors of the Ras signalling pathway, such as farnesyl transferase inhibitor 1 and PD98069, effectively suppressed HSV-1 infection of ras-transformed cells. Enhanced permissiveness of the transformed cells was linked to the inhibition of virus-induced activation (phosphorylation) of the double-stranded RNA-activated protein kinase (PKR), thereby allowing viral transcripts to be translated in these cells. An HSV-1-derived oncolytic mutant, R3616, was also found to infect preferentially both transformed cells and PKR-/- (but not PKR+/+) mouse embryo fibroblasts. These observations suggest that HSV-1 specifically targets cells with an activated Ras signalling pathway, and have important ramifications in the use of engineered HSV in cancer therapy, the development of strategies against HSV infections, and the controversial role of HSV in human cancers.