Division of Virology, Aichi Cancer Center Research Institute, Chikusa-ku, Nagoya, Japan.
Cell Cycle. 2010 Feb 15;9(4):807-14. doi: 10.4161/cc.9.4.10675. Epub 2010 Feb 17.
Expression of Epstein-Barr Virus BZLF1, a key protein initiating the switch from latent to lytic infection, is known to cause cell growth arrest by accumulating p53 and p21(WAF1/CIP1) in epithelial cells, but its molecular mechanism remains elusive. We found here that the BZLF1 protein stimulates p53 binding to its recognition sequence. The BZLF1 accelerated the rate of p53-DNA complex formation through the interaction with p53 protein and also enhanced p53-specific transcription in vitro. Furthermore, p53 protein was found to bind to its target promoter regions specifically in the early stages of lytic replication. Overexpression of p53 at the early stages of lytic replication enhanced viral genome replication, supporting the idea that p53 plays an important role in the initiation steps of EBV replication. Taking the independent role of BZLF1 on p53 degradation into consideration, we propose that the BZLF1 protein regulates p53 and its target gene products in two distinctive manners; transient induction of p53 at the early stages for the initiation of viral productive replication and p53 degradation at the later stages for S-phase like environment preferable for viral replication.
已知 Epstein-Barr 病毒（EBV）BZLF1 蛋白的表达会导致潜伏感染向裂解感染的转变，其通过在上皮细胞中积累 p53 和 p21（WAF1/CIP1）来引起细胞生长停滞，但具体的分子机制仍不清楚。我们在这里发现，BZLF1 蛋白刺激 p53 与其识别序列结合。BZLF1 通过与 p53 蛋白相互作用，加速了 p53-DNA 复合物的形成速度，并在体外增强了 p53 特异性转录。此外，还发现 p53 蛋白在裂解复制的早期阶段特异性地结合到其靶启动子区域。在裂解复制的早期阶段过表达 p53 可增强病毒基因组的复制，这支持了 p53 在 EBV 复制起始步骤中发挥重要作用的观点。考虑到 BZLF1 对 p53 降解的独立作用，我们提出 BZLF1 蛋白以两种不同的方式调节 p53 及其靶基因产物；在病毒产生性复制的起始阶段短暂诱导 p53，以及在后期降解 p53 以促进有利于病毒复制的 S 期样环境。
