Epstein-Barr virus latent membrane protein 1 blocks p53-mediated apoptosis through the induction of the A20 gene
Epstein-Barr virus latent membrane protein 1 blocks p53-mediated apoptosis through the induction of the A20 gene
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DOI：
10.1128/jvi.70.12.8653-8659.1996
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发表时间：
1996-12-01
影响因子：
5.4
通讯作者：
RaabTraub, N
中科院分区：
文献类型：
--
作者：
Fries, KL;Miller, WE;RaabTraub, N
两种eb病毒（EBV）相关的恶性肿瘤，鼻咽癌和移植后淋巴瘤，p53肿瘤抑制基因很少发生突变，这表明一种病毒蛋白干扰p53的功能。EBV癌基因LMP1诱导细胞抗凋亡基因bcl-2和A20的表达，从而干扰p53介导的细胞凋亡。制备了p53-null上皮细胞系H1299的两个衍生物，其中一个（H1299-p53）稳定表达温度敏感（ts） p53蛋白，另一个（H1299-p53 +LMP1）稳定表达ts-p53和潜伏膜蛋白1 （LMP1）。在允许的温度下，H1299-p53细胞系中的p53蛋白以不依赖lmp1的方式转录激活其两个靶基因，即周期蛋白依赖性激酶抑制剂p21和mdm2基因产物。在允许温度下提取血清后，p53介导的细胞凋亡在50%至60%的细胞中被诱导。而在稳定表达LMP1的H1299-p53细胞系中，只有20 - 25%的细胞发生凋亡。虽然LMP1的稳定表达不影响bcl-2家族成员在这些细胞中的水平，但它确实诱导了A20的表达。A20在H1299-p53细胞系中稳定表达抑制p53介导的细胞凋亡相当于LMP1的抑制作用。A20的诱导可能是LMP1保护ebv感染的上皮细胞免受p53介导的凋亡能力的基础。
Two Epstein-Barr virus (EBV)-associated malignancies, nasopharyngeal carcinoma and posttransplant lymphoma, rarely have mutations in the p53 tumor suppressor gene, suggesting that a viral protein interferes with p53 function. The EBV oncogene, LMP1, induces expression of the cellular antiapoptotic genes bcl-2 and A20 and could in this way interfere with p53-mediated apoptosis. Two derivatives of the p53-null epithelial cell line H1299 were prepared, one of which (H1299-p53) stably expressed a temperature-sensitive (ts) p53 protein, and another (H1299-p53 +LMP1) which stably expressed both ts-p53 and latent membrane protein 1 (LMP1). At the permissive temperature, the p53 protein in the H1299-p53 cell line transcriptionally activated two of its target genes, the cyclin-dependent kinase inhibitor p21 and the mdm2 gene product, in an LMP1-independent manner. Upon serum withdrawal at the permissive temperature, p53-mediated apoptosis was induced in 50 to 60% of the cells. In the H1299-p53 cell line which stably expressed LMP1, however, only 20 to 25% of the cells underwent apoptosis. While stable expression of LMP1 did not affect levels of bcl-2 family members in these cells, it did induce expression of A20. Stable expression of A20 in the H1299-p53 cell line inhibited p53-mediated apoptosis equivalent to inhibition by LMP1. The induction of A20 may underlie the ability of LMP1 to protect EBV-infected epithelial cells from p53-mediated apoptosis.