Distinct p53, p53: LANA, and LANA Complexes in Kaposi's Sarcoma-Associated Herpesvirus Lymphomas
Distinct p53, p53: LANA, and LANA Complexes in Kaposi's Sarcoma-Associated Herpesvirus Lymphomas
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DOI：
10.1128/jvi.01321-09
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发表时间：
2010-04-01
影响因子：
5.4
通讯作者：
Dittmer, Dirk P.
中科院分区：
文献类型：
--
作者：
Chen, Wuguo;Hilton, Isaac B.;Dittmer, Dirk P.
p53在原发性渗出性淋巴瘤（PEL）中的作用是复杂的。卡波济肉瘤相关疱疹病毒（KSHV）的潜伏相关核抗原（拉娜）结合p53。尽管有这种相互作用，我们发现p53在PEL中是有功能的，即，能够响应DNA损伤诱导凋亡（C. E. Petre，S. H. Sin和D. P. Dittmer，J. Virol. 81：1912-1922，2007），并且HDM 2过表达。为了进一步阐明拉娜、p53和hdm 2之间的关系，我们通过柱层析从PEL中纯化了拉娜复合物。这证实了拉娜结合p53。然而，拉娜：p53复合物与hdm 2：p53和p53：p53复合物相比是少数。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、拉娜：p53和拉娜：拉娜复合物共存于PEL中，并且每种蛋白质都能够与其同源DNA元件结合。这些数据表明，在正常条件下，p53在PEL中是无活性的，因此允许指数生长，但是这种失活是由拉娜、hdm 2和p53的相对化学计量驱动的。如果p53被DNA损伤或nutlin-3a激活，复合物福尔斯很容易分解，p53就扮演了基因组监护人的角色。
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.