The retinoblastoma tumor suppressor promotes efficient human cytomegalovirus lytic replication.
The retinoblastoma tumor suppressor promotes efficient human cytomegalovirus lytic replication.
复制标题
视网膜母细胞瘤肿瘤抑制因子促进有效的人巨细胞病毒裂解复制。
DOI：
10.1128/jvi.00175-15
复制
发表时间：
2015
影响因子：
5.4
通讯作者：
Kalejta,RobertF
中科院分区：
文献类型：
--
作者：
VanDeusen,HalenaR;Kalejta,RobertF
视网膜母细胞瘤（Rb）肿瘤抑制因子控制细胞周期、DNA损伤、凋亡和代谢途径。DNA肿瘤病毒癌蛋白通过诱导Rb降解或物理破坏Rb与其无数结合蛋白之间的复合物来降低Rb功能。人巨细胞病毒（HCMV）是一种β疱疹病毒，正在研究其在人类癌症中的潜在作用，其编码多种以不同方式抑制Rb的裂解期蛋白，从而导致Rb水平和/或活性降低将有益于HCMV裂解感染的假设。奇怪的是，我们发现Rb基因敲低感染前，无论是短暂的或组成性的，损害HCMV裂解感染在多个阶段，特别是病毒DNA复制，后期蛋白质表达，和感染性病毒粒子的生产。Rb的差异修饰形式的存在，HCMV蛋白与Rb相互作用的时间和功能上不同的方式，和Rb对有效HCMV裂解性复制的必要性联合收割机，突出了病毒和这一关键肿瘤抑制因子之间的复杂关系。细胞肿瘤抑制蛋白然而，随后的工作，包括这里描述的使用人巨细胞病毒的实验，证明了一个更微妙的相互作用，包括有效的病毒复制的细胞肿瘤抑制剂的必要性。了解细胞肿瘤抑制因子对病毒感染的积极影响可能会揭示这些研究充分但尚未完全了解的蛋白质的新活性。溶瘤病毒疗法的基础是在肿瘤抑制功能可能受损的转化细胞中选择性复制病毒。了解肿瘤抑制因子如何支持病毒感染可能允许产生具有更大选择性的肿瘤细胞复制和杀伤的修饰的溶瘤病毒。
The retinoblastoma (Rb) tumor suppressor controls cell cycle, DNA damage, apoptotic, and metabolic pathways. DNA tumor virus oncoproteins reduce Rb function by either inducing Rb degradation or physically disrupting complexes between Rb and its myriad binding proteins. Human cytomegalovirus (HCMV), a betaherpesvirus being investigated for potential roles in human cancers, encodes multiple lytic-phase proteins that inactivate Rb in distinct ways, leading to the hypothesis that reduced Rb levels and/or activity would benefit HCMV lytic infection. Paradoxically, we found that Rb knockdown prior to infection, whether transient or constitutive, impaired HCMV lytic infection at multiple stages, notably viral DNA replication, late protein expression, and infectious virion production. The existence of differentially modified forms of Rb, the temporally and functionally distinct means by which HCMV proteins interact with Rb, and the necessity of Rb for efficient HCMV lytic replication combine to highlight the complex relationship between the virus and this critical tumor suppressor.IMPORTANCEInitial work examining viral protein modulation of cell cycle progression and oncogenic transformation revealed that these proteins inactivated the function of cellular tumor suppressor proteins. However, subsequent work, including experiments described here using human cytomegalovirus, demonstrate a more nuanced interaction that includes the necessity of cellular tumor suppressors for efficient viral replication. Understanding the positive impacts that cellular tumor suppressors have on viral infections may reveal new activities of these well-studied yet incompletely understood proteins. The basis for oncolytic viral therapy is the selective replication of viruses in transformed cells in which tumor suppressor function may be compromised. Understanding how tumor suppressors support viral infections may allow for the generation of modified oncolytic viruses with greater selective tumor cell replication and killing.