Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, Center for AIDS Research, University of North Carolina at Chapel Hill, CB no. 7290, 715 Mary Ellen Jones Bldg., Chapel Hill, NC 27599-7290, USA.
J Virol. 2010 Apr;84(8):3898-908. doi: 10.1128/JVI.01321-09. Epub 2010 Feb 3.
The role of p53 in primary effusion lymphoma (PEL) is complicated. The latency-associated nuclear antigen (LANA) of Kaposi's sarcoma-associated herpesvirus (KSHV) binds p53. Despite this interaction, we had found that p53 was functional in PEL, i.e., able to induce apoptosis in response to DNA damage (C. E. Petre, S. H. Sin, and D. P. Dittmer, J. Virol. 81:1912-1922, 2007), and that hdm2 was overexpressed. To further elucidate the relationship between LANA, p53, and hdm2, we purified LANA complexes from PEL by column chromatography. This confirmed that LANA bound p53. However, the LANA:p53 complexes were a minority compared to hdm2:p53 and p53:p53 complexes. The half-life of p53 was not extended, which is in contrast to the half-life of simian virus 40 T antigen-transformed cells. p53:p53, LANA:p53, and LANA:LANA complexes coexisted in PEL, and each protein was able to bind to its cognate DNA element. These data suggest that under normal conditions, p53 is inactive in PEL, thus allowing for exponential growth, but that this inactivation is driven by the relative stoichiometries of LANA, hdm2, and p53. If p53 is activated by DNA damage or nutlin-3a, the complex falls apart easily, and p53 exercises its role as guardian of the genome.
p53 在原发性渗出性淋巴瘤（PEL）中的作用很复杂。卡波济肉瘤相关疱疹病毒（KSHV）的潜伏相关核抗原（LANA）与 p53 结合。尽管存在这种相互作用，但我们发现 p53 在 PEL 中具有功能，即能够响应 DNA 损伤诱导细胞凋亡（C. E. Petre、S. H. Sin 和 D. P. Dittmer，J. Virol. 81:1912-1922, 2007），并且 hdm2 过表达。为了进一步阐明 LANA、p53 和 hdm2 之间的关系，我们通过柱层析从 PEL 中纯化 LANA 复合物。这证实了 LANA 与 p53 结合。然而，与 hdm2:p53 和 p53:p53 复合物相比，LANA:p53 复合物是少数。p53 的半衰期没有延长，这与猿猴病毒 40 T 抗原转化细胞的半衰期相反。p53:p53、LANA:p53 和 LANA:LANA 复合物在 PEL 中共存，并且每种蛋白质都能够与它的同源 DNA 元件结合。这些数据表明，在正常情况下，p53 在 PEL 中不活跃，从而允许指数生长，但这种失活是由 LANA、hdm2 和 p53 的相对浓度决定的。如果 p53 被 DNA 损伤或 nutlin-3a 激活，复合物就很容易解体，p53 就会发挥其作为基因组守护者的作用。
