Herpes simplex virus type 1 infection imposes a G1/S block in asynchronously growing cells and prevents G1 entry in quiescent cells
Herpes simplex virus type 1 infection imposes a G1/S block in asynchronously growing cells and prevents G1 entry in quiescent cells
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DOI：
10.1006/viro.1999.0147
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发表时间：
2000-02-15
期刊：
影响因子：
3.7
通讯作者：
Bachenheimer, SL
中科院分区：
文献类型：
--
作者：
Ehmann, GL;McLean, TI;Bachenheimer, SL
1 型单纯疱疹病毒 (HSV-1) 感染至少以两种方式破坏细胞周期调节。首先，感染静止的人胚胎肺细胞并同时重新添加血清，导致视网膜母细胞瘤蛋白 pRb 的细胞周期蛋白 D/细胞周期蛋白依赖性激酶 (CDK) 4,6 特异性和细胞周期蛋白 E/CDK2 特异性磷酸化受到抑制。细胞周期蛋白 D/CDK4,6 激酶活性的抑制与细胞周期蛋白 D1 蛋白的丢失以及 CDK4 和 CDK6 无法转位至细胞核相对应。未能检测到细胞周期蛋白 E/CDK2 激酶活性会伴随着细胞周期蛋白 E 蛋白的丢失和 CDK2 无法转位至细胞核。口袋蛋白 p130 的水平持续存在，而 p107 没有积累。由于这些对细胞周期蛋白激酶的影响，G(o) 感染的细胞无法重新进入细胞周期。在异步分裂的细胞培养物中观察到第二种类型的 HSV 诱导的细胞周期失调。在人胚胎肺细胞以及其他两种人细胞系：C33 和 U2OS 中观察到先前存在的细胞周期蛋白 E/CDK2 和细胞周期蛋白 A/CDK2 活性的快速抑制。 HSV-1 立即早期基因表达对于抑制 CDK2 激酶活性是必要的。细胞周期蛋白和 CDK 亚基蛋白水平、细胞内定位和复合物稳定性不受感染影响。此外，细胞周期蛋白依赖性激酶抑制剂p27和p21的水平不受HSV-1的影响。先前的实验表明，在异步感染的细胞中，低磷酸化的 pRb 和袋蛋白-E2F 复合物积累，细胞 DNA 合成迅速受到抑制。结合目前的结果，这表明 HSV-1 已经进化出阻止 G 细胞通过限制点和 S 细胞完成一轮 DNA 复制的机制。 (C) 2000 年学术出版社。
Herpes simplex virus type 1 (HSV-1) infection disrupted cell cycle regulation in at least two ways. First, infection of quiescent human embryonic lung cells simultaneously with readdition of serum caused inhibition of cyclin D/cyclin-dependent kinase (CDK) 4,6-specific and cyclin E/CDK2-specific phosphorylation of the retinoblastoma protein pRb. The inhibition of cyclin D/CDK4,6 kinase activity corresponded to a loss of cyclin D1 protein and a failure of CDK4 and CDK6 to translocate to the nucleus. Failure to detect cyclin E/CDK2 kinase activity was accompanied by a loss of cyclin E protein and a failure of CDK2 to translocate to the nucleus. Levels of pocket protein p130 persisted, whereas p107 did not accumulate. As a result of these effects on cyclin kinase, G(o)-infected cells failed to reenter the cell cycle. The second type of HSV-induced cell cycle dysregulation was observed in asynchronously dividing cell cultures. A rapid inhibition of preexisting cyclin E/CDK2 and cyclin A/CDK2 activities was observed in human embryonic lung cells, as well as two other human cell lines: C33 and U2OS. HSV-1 immediate-early gene expression was necessary for the inhibition of CDK2 kinase activity. Cyclin and CDK subunit protein levels, intracellular localization, and complex stability were unaffected by infection. In addition, levels of cyclin-dependent kinase inhibitors, p27 and p21, were not affected by HSV-1. Previous experiments demonstrated that in asynchronous infected cells, hypophosphorylated pRb and pocket protein-E2F complexes accumulated, and cellular DNA synthesis was rapidly inhibited. Coupled with the present results, this indicates that HSV-1 has evolved mechanisms for preventing cells in G, from proceeding through the restriction point and for cells in S from completing a round of DNA replication. (C) 2000 Academic Press.