MDM2-Dependent Inhibition of p53 Is Required for Epstein-Barr Virus B-Cell Growth Transformation and Infected-Cell Survival
MDM2-Dependent Inhibition of p53 Is Required for Epstein-Barr Virus B-Cell Growth Transformation and Infected-Cell Survival
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DOI：
10.1128/jvi.01681-08
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发表时间：
2009-03-15
影响因子：
5.4
通讯作者：
Luftig, Micah A.
中科院分区：
文献类型：
--
作者：
Forte, Eleonora;Luftig, Micah A.
Epstein-Barr病毒（EBV）原代B淋巴细胞到无限期增殖的淋巴细胞细胞系（LCLS）的生长转化取决于在潜伏期表达的病毒蛋白的协同活性。 EBV将静止的B细胞驱动到S相，因此，激活了宿主反应，其中包括p53及其靶基因的表达。由于LCLS保留了野生型p53，因此确定p53途径在控制已建立的LCL生长和EBV介导的原代B细胞转化方面可能有什么贡献。我们发现，使用小分子Nutlin-3通过其主要泛素连接酶之一MDM2的化学拮抗作用来解放p53，导致已建立的LCLS凋亡，并抑制了EBV介导的原代B细胞的转化。潜在p53诱导靶基因与凋亡相关的靶基因。此外，MDM2拮抗作用与NF-kappa B抑制在杀死LCL中。 NF-KAPPA B对于增加稳态MDM2蛋白水平而不是影响p53依赖性转录很重要，这表明LCLS在存在启动的p53途径的情况下可以生存。 EBV感染细胞的Nutlin敏感性提供了一种新的系统，用于研究决定LCL存活并调节EBV转化的途径。最后，可以将MDM2拮抗剂视为表达野生型p53的EBV相关的恶性肿瘤的治疗干预。
Epstein-Barr virus (EBV) growth transformation of primary B lymphocytes into indefinitely proliferating lymphoblastoid cell lines (LCLs) depends on the concerted activities of a subset of viral proteins expressed during latency. EBV drives quiescent B cells into S phase, and consequently, a host response is activated that includes expression of p53 and its target genes. Since LCLs retain wild-type p53, it was of interest to determine what contribution the p53 pathway may have in controlling established LCL growth and EBV-mediated transformation of primary B cells. We found that liberation of p53 through chemical antagonism of one of its major ubiquitin ligases, MDM2, using the small-molecule Nutlin-3 led to apoptosis of established LCLs and suppressed EBV-mediated transformation of primary B cells. The activation of latent p53 induced target genes associated with apoptosis. Furthermore, MDM2 antagonism synergized with NF-kappa B inhibition in killing LCLs. NF-kappa B was important to increase steady-state MDM2 protein levels rather than in affecting p53-dependent transcription, suggesting a unique mechanism by which LCLs survive in the presence of a primed p53 pathway. Nutlin sensitivity of EBV-infected cells provides a novel system for studying the pathways that dictate LCL survival and regulate EBV transformation. Finally, MDM2 antagonists may be considered for therapeutic intervention in EBV-associated malignancies expressing wild-type p53.