Viral and cell cycle-regulated kinases in cytomegalovirus-induced pseudomitosis and replication.
Viral and cell cycle-regulated kinases in cytomegalovirus-induced pseudomitosis and replication.
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DOI：
10.1371/journal.ppat.0030006
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发表时间：
2007-01
期刊：
影响因子：
6.7
通讯作者：
Mocarski ES
中科院分区：
文献类型：
--
作者：
Hertel L;Chou S;Mocarski ES
在人巨细胞病毒感染期间发生假有丝分裂过程，其看起来类似于细胞有丝分裂，但涉及多个纺锤体极的形成、异常凝聚和染色体DNA的错误定位。这一过程与病毒复制和感染过程中细胞周期调控的关系一直知之甚少。在所有检查的病毒株中，假丝分裂始终在感染后期达到峰值，但使用一种常见的实验室菌株变体（AD 169 varATCC）时，假丝分裂的频率总体最高（30%至35%的细胞）。细胞周期蛋白依赖性激酶1（Cdk 1）在假有丝分裂中起着至关重要的作用，反映了其在常规有丝分裂中的作用。显性负Cdk 1抑制和野生型Cdk 1刺激这一过程，然而，病毒产量保持不变，无论假有丝分裂水平。靛玉红-3 ′-单肟对细胞周期调节激酶（Cdk 1/Cdk 2/Cdk 5/Cdk 9）的广泛抑制作用显著降低了病毒产量，并与病毒UL 97激酶抑制剂Maribavir协同作用。因此，Cdk 1是驱动假有丝分裂所必需的，而病毒和细胞周期调节激酶的组合在病毒复制过程中是重要的。感染全球大多数人的人类疱疹病毒巨细胞病毒对细胞生长和分裂产生刺激作用，创造了一个与许多可能在病毒性疾病中重要的致癌病毒相似的环境。在以前的工作中，我们发现病毒感染刺激细胞进入模拟细胞分裂或有丝分裂的异常状态，但阻止子细胞的形成。在这里，异常状态（假有丝分裂）被证明取决于病毒事件，驱动高水平的细胞酶细胞周期蛋白依赖性激酶1（Cdk 1），通常与通过细胞分裂的进展。虽然Cdk 1本身对病毒复制水平没有可检测的影响，但宿主细胞周期蛋白依赖性激酶在病毒复制中与病毒编码的蛋白激酶（UL 97）起重叠作用。这些宿主和病毒激酶的特异性抑制剂被用来证明Cdk 1是驱动假有丝分裂所必需和充分的;然而，病毒以及细胞周期调节激酶对有效的病毒复制很重要。
A process of pseudomitosis occurs during human cytomegalovirus infection that appears similar to cellular mitosis but involves the formation of multiple spindle poles, abnormal condensation, and mislocalization of chromosomal DNA. The relationship of this process to viral replication and cell cycle regulation during infection has been poorly understood. Pseudomitosis consistently peaks at late times of infection in all viral strains examined but at overall highest frequencies (30% to 35% of cells) using one common laboratory strain variant (AD169varATCC). Cyclin-dependent kinase 1 (Cdk1) plays a crucial role in pseudomitosis, mirroring its role in conventional mitosis. Dominant negative Cdk1 inhibits and wild-type Cdk1 stimulates this process; however, viral yields remain the same regardless of pseudomitosis levels. Broad inhibition of cell cycle−regulated kinases (Cdk1/Cdk2/Cdk5/Cdk9) with indirubin-3′-monoxime substantially decreases viral yields and synergizes with the viral UL97 kinase inhibitor, maribavir. Thus, Cdk1 is necessary and sufficient to drive pseudomitosis, whereas a combination of viral and cell cycle−regulated kinases is important during viral replication. The human herpesvirus cytomegalovirus, which infects most people worldwide, orchestrates a stimulatory effect on cell growth and division, creating an environment that appears similar to many cancer-causing viruses that may be important in viral disease. In previous work, we discovered that viral infection stimulates cells to proceed to an abnormal state mimicking cell division or mitosis but blocks the formation of daughter cells. Here the abnormal state (pseudomitosis) is shown to depend on viral events that drive high levels of the cellular enzyme cyclin-dependent kinase 1 (Cdk1), normally associated with progression through cell division. Although Cdk1 by itself exerts no detectable influence on viral replication levels, host cell cyclin-dependent kinases play an overlapping role with the virus-encoded protein kinase (UL97) in viral replication. Specific inhibitors of these host and viral kinases are used to demonstrate that Cdk1 is necessary and sufficient to drive pseudomitosis; however, viral as well as cell cycle−regulated kinases are important for efficient viral replication.
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DOI：
10.1073/pnas.200375297
发表时间：
2000-09-26
影响因子：
11.1
作者：
Advani, SJ;Weichselbaum, RR;Roizman, B
通讯作者：
Roizman, B
影响因子：
3.7
作者：
Bresnahan, WA;Boldogh, I;Albrecht, T
通讯作者：
Albrecht, T
影响因子：
21.3
作者：
Hoessel, R;Leclerc, S;Meijer, L
通讯作者：
Meijer, L
影响因子：
3.7
作者：
Bresnahan, WA;Boldogh, I;Albrecht, T
通讯作者：
Albrecht, T
影响因子：
4.9
作者：
Chou, SW;Van Wechel, LC;Marousek, GI
通讯作者：
Marousek, GI