E2F proteins are posttranslationally modified concomitantly with a reduction in nuclear binding activity in cells infected with herpes simplex virus 1
E2F proteins are posttranslationally modified concomitantly with a reduction in nuclear binding activity in cells infected with herpes simplex virus 1
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DOI：
10.1128/jvi.74.17.7842-7850.2000
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发表时间：
2000-09-01
影响因子：
5.4
通讯作者：
Roizman, B
中科院分区：
文献类型：
--
作者：
Advani, SJ;Weichselbaum, RR;Roizman, B
细胞周期从G(1)期向S期的转变需要细胞周期蛋白依赖性激酶4(CDK4)和CDK2的顺序激活，使视网膜母细胞瘤蛋白磷酸化，导致E2F的释放。游离E2F上调S期和细胞周期进程相关基因的转录。最近来自该实验室和其他实验室的研究表明，单纯疱疹病毒1在感染早期稳定细胞周期蛋白D3，病毒复制的早期事件对一些CDK的抑制剂敏感，另一方面CDK2不被激活。在这里，我们报道了E2F家族成员在Hep-2和HeLa细胞以及静止的血清饥饿、接触抑制的人肺成纤维细胞中的地位的研究。结果表明：(1)在感染后8h或之后，E2F-1和E2F-5被翻译后修饰和/或从细胞核移位到细胞质；(Ii)E2F-4过度磷酸化；(Iii)总的来说，E2F与同源DNA位点的结合在感染后后期减少。这些结果与上面提到的结果一致，表明在感染后期，S期基因的激活被翻译后修饰和E2F家族成员移位到不活跃的隔室以及缺乏活性的CDK2所阻断。在感染时不处于S期的静止的人肺成纤维细胞中，E2F也被翻译后修饰，这表明特定的病毒基因产物负责E2F家族成员的修饰，并提出了在感染细胞中，S期基因的激活是病毒感染的早期事件，然后在晚期被关闭的可能性。这与细胞周期蛋白D3稳定的时间和被CDKs抑制剂阻断的事件相一致。
The transition from G(1) to S phase in the cell cycle requires sequential activation of cyclin-dependent kinase 4 (cdk4) and cdk2, which phosphorylate the retinoblastoma protein, causing the release of E2F. Free E2F upregulates the transcription of genes involved in S phase and cell cycle progression. Recent studies from this and other laboratories have shown that herpes simplex virus 1 stabilizes cyclin D3 early in infection and that early events in viral replication are sensitive to inhibitors of some cdks, On the other hand cdk2 is not activated. Here we report studies on the status of members of E2F family in cycling HEp-2 and HeLa cells and quiescent serum-starved, contact-inhibited human lung fibroblasts. The results show that (i) at 8 h postinfection or thereafter, E2F-1 and E2F-5 were posttranslationally modified and/or translocated from nucleus to the cytoplasm, (ii) E2F-4 was hyperphophorylated, and (iii) overall, E2F binding to cognate DNA sites was decreased at late times after infection. These results concurrent with those cited above indicate that late in infection activation of S-phase genes is blocked both by posttranslational modification and translocation of members of E2F family to inactive compartments and by the absence of active cdk2. The observation that E2F were also posttranslationally modified in quiescent human lung fibroblasts that were not in S phase at the time of infection suggests that specific viral gene products are responsible for modification of the members of E2F family and raises the possibility that in infected cells, activation of the S phase gene is an early event in viral infection and is then shut off at late times. This is consistent with the timing of stabilization of cyclin D3 and the events blocked by inhibitors of cdks.