Activated MEK suppresses activation of PKR and enables efficient replication and in vivo oncolysis by Δγ134.5 mutants of herpes simplex virus 1
Activated MEK suppresses activation of PKR and enables efficient replication and in vivo oncolysis by Δγ134.5 mutants of herpes simplex virus 1
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DOI：
10.1128/jvi.80.3.1110-1120.2006
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发表时间：
2006-02-01
影响因子：
5.4
通讯作者：
Weichselbaum, RR
中科院分区：
文献类型：
--
作者：
Smith, KD;Mezhir, JJ;Weichselbaum, RR
单纯疱疹病毒突变株缺乏γ(1)34.5基因，对正常组织没有破坏性，但在人类肿瘤细胞中是有效的细胞杀伤剂，其中双链RNA依赖的蛋白激酶(PKR)的激活受到抑制。因此，在12个基因定义的癌细胞系中复制Delta Gamma(1)34.5突变体(R3616)与PKR抑制有关，而与RAS的基因型无关。对转导了显性负性MEK(DnMEK)和结构性活性MEK(CaMEK)的两株细胞的广泛分析表明，在R3616突变感染的细胞中，dnMEK激活了PKR并降低了病毒产量，而caMEK抑制了PKR，并在体外或在小鼠异种移植瘤中实现了更好的病毒复制和细胞破坏。结果表明，激活的MEK介导了对PKR的抑制，MEK的状态预测了Delta Gamma(1)34.5突变病毒在肿瘤细胞内复制和破坏的能力。
Herpes simplex virus mutants lacking the gamma(1)34.5 gene are not destructive to normal tissues but are potent cytolytic agents in human tumor cells in which the activation of double-stranded RNA-dependent protein kinase (PKR) is suppressed. Thus, replication of a Delta gamma(1)34.5 mutant (R3616) in 12 genetically defined cancer cell lines correlates with suppression of PKR but not with the genotype of RAS. Extensive analyses of two cell lines transduced with either dominant negative MEK (dnMEK) or constitutively active MEK (caMEK) indicated that in R3616 mutant-infected cells dnMEK enabled PKR activation and decreased virus yields, whereas caMEK suppressed PKR and enabled better viral replication and cell destruction in transduced cells in vitro or in mouse xenografts. The results indicate that activated MEK mediates the suppression of PKR and that the status of MEK predicts the ability of Delta gamma(1)3 4.5 mutant viruses to replicate in and destroy tumor cells.