Epstein-Barr Virus Latent Membrane Protein 2A Contributes to Anoikis Resistance through ERK Activation
Epstein-Barr Virus Latent Membrane Protein 2A Contributes to Anoikis Resistance through ERK Activation
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DOI：
10.1128/jvi.01089-13
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发表时间：
2013-07-01
影响因子：
5.4
通讯作者：
Samanta, Mrinal
中科院分区：
文献类型：
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作者：
Iwakiri, Dai;Minamitani, Takeharu;Samanta, Mrinal
EB 病毒 (EBV) 与多种恶性肿瘤相关，包括上皮癌。在本研究中，我们利用EBV转化的上皮细胞分析了EBV感染对上皮细胞的影响。在 EBV 阳性细胞中，细胞外信号调节激酶 (ERK) 途径被组成型激活。抑制 ERK 活性会导致失巢凋亡抵抗力降低；因此，EBV 阳性细胞比 EBV 阴性细胞更能抵抗失巢凋亡（一种由细胞脱离诱导的细胞凋亡）。在 EBV 阳性细胞中表达的病毒基因中，潜在膜蛋白 2A (LMP2A) 负责诱导 ERK 介导的失巢凋亡抵抗，尽管 LMP2A 在 EBV 阳性细胞中的表达水平比 EBV 转化的 B 细胞低得多。进一步分析表明，LMP2A 通过蛋白酶体降解下调失巢凋亡介质 Bim 依赖于基于免疫受体酪氨酸的激活基序 (ITAM)。这些发现表明 LMP2A 介导的 ERK 激活参与 EBV 相关上皮恶性肿瘤的产生。
Epstein-Barr virus (EBV) is associated with various malignancies, including epithelial cancers. In this study, we analyzed the effect of EBV infection on epithelial cells by using EBV-converted epithelial cells. In EBV-positive cells, the extracellular signal-regulated kinase (ERK) pathway is constitutively activated. Inhibition of ERK activity leads to reduced anoikis resistance; therefore, EBV-positive cells are more resistant to anoikis, a type of apoptosis induced by cell detachment, than are EBV-negative cells. Among the viral genes expressed in EBV-positive cells, the latent membrane protein 2A (LMP2A) is responsible for induction of ERK-mediated anoikis resistance, although the expression level of LMP2A is much lower in EBV-positive cells than in EBV-transformed B cells. Further analysis demonstrated that LMP2A downregulation of the proanoikis mediator Bim through proteasomal degradation is dependent on the immunoreceptor tyrosine-based activation motif (ITAM). These findings suggest that LMP2A-mediated ERK activation is involved in the generation of EBV-associated epithelial malignancies.