EBV-encoded LMP1 upregulates Igκ 3'enhancer activity and Igκ expression in nasopharyngeal cancer cells by activating the Ets-1 through ERKs signaling.
EBV-encoded LMP1 upregulates Igκ 3'enhancer activity and Igκ expression in nasopharyngeal cancer cells by activating the Ets-1 through ERKs signaling.
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DOI：
10.1371/journal.pone.0032624
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Cao Y
中科院分区：
文献类型：
--
作者：
Liu H;Duan Z;Zheng H;Hu D;Li M;Tao Y;Bode AM;Dong Z;Cao Y
越来越多的证据表明，上皮癌细胞，包括鼻咽癌（NPC）细胞，表达免疫球蛋白（Ig）。我们以前发现，鼻咽癌细胞中κ轻链蛋白的表达可以通过EB病毒编码的潜伏膜蛋白1（LMP 1）上调。在本研究中，我们使用NPC细胞系作为模型，发现LMP 1增强的kappa产生与ERK磷酸化的升高相对应。PD 98059减弱LMP 1诱导的ERK磷酸化，导致κ轻链表达降低。ERK特异性小干扰RNA钝化LMP 1诱导的κ轻链基因表达荧光素酶报告基因分析表明免疫球蛋白κ 3′增强子（3′Eκ）在表达IGκ的NPC细胞中具有活性，LMP 1上调NPC细胞中3′Eκ的活性。此外，对3′Eκ中PU结合位点的突变分析和PD 98059对MEK/ERK通路的抑制表明，PU位点是功能性的，LMP 1增强的3′Eκ活性部分受该位点的调节。PD 98059处理还导致LMP 1诱导的Ets-1表达和磷酸化的浓度依赖性抑制，这与LMP 1诱导的ERK磷酸化和κ轻链表达的剂量依赖性减弱相对应。小干扰RNA对内源性Ets-1的抑制伴随着IG κ轻链表达的降低。用NPC细胞核提取物进行的凝胶迁移试验表明，转录因子Ets-1在体外被LMP 1募集到3′Eκ内的PU基序。ChIP分析进一步证明Ets-1与细胞中3′Eκ的PU基序结合。这些结果表明，LMP 1通过ERK信号通路激活Ets-1转录因子，上调3′Eκ活性和kappa基因表达。我们的研究为kappa表达的一种新的调控机制提供了证据，通过这种机制，病毒编码的蛋白通过激活非B上皮癌细胞中的转录因子来激活kappa 3′增强子。
Accumulating evidence indicates that epithelial cancer cells, including nasopharyngeal carcinoma (NPC) cells, express immunoglobulins (Igs). We previously found that the expression of the kappa light chain protein in NPC cells can be upregulated by the EBV-encoded latent membrane protein 1 (LMP1). In the present study, we used NPC cell lines as models and found that LMP1-augmented kappa production corresponds with elevations in ERKs phosphorylation. PD98059 attenuates LMP1-induced ERKs phosphorylation resulting in decreased expression of the kappa light chain. ERK-specific small interfering RNA blunts LMP1-induced kappa light chain gene expression. Luciferase reporter assays demonstrate that immunoglobulin κ 3′ enhancer (3′Eκ) is active in Igκ-expressing NPC cells and LMP1 upregulates the activity of 3′Eκ in NPC cells. Moreover, mutation analysis of the PU binding site in 3′Eκ and inhibition of the MEK/ERKs pathway by PD98059 indicate that the PU site is functional and LMP1-enhanced 3′Eκ activity is partly regulated by this site. PD98059 treatment also leads to a concentration-dependent inhibition of LMP1-induced Ets-1 expression and phosphorylation, which corresponds with a dose-dependent attenuation of LMP1-induced ERK phosphorylation and kappa light chain expression. Suppression of endogenous Ets-1 by small interfering RNA is accompanied by a decrease of Ig kappa light chain expression. Gel shift assays using nuclear extracts of NPC cells indicate that the transcription factor Ets-1 is recruited by LMP1 to the PU motif within 3′Eκ in vitro. ChIP assays further demonstrate Ets-1 binding to the PU motif of 3′Eκ in cells. These results suggest that LMP1 upregulates 3′Eκ activity and kappa gene expression by activating the Ets-1 transcription factor through the ERKs signaling pathway. Our studies provide evidence for a novel regulatory mechanism of kappa expression, by which virus-encoded proteins activate the kappa 3′ enhancer through activating transcription factors in non-B epithelial cancer cells.
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影响因子：
4.4
作者：
Hashimoto, S;Nishizumi, H;Sakano, H
通讯作者：
Sakano, H
影响因子：
4.8
作者：
Liu, Hai-dan;Zheng, Hui;Cao, Ya
通讯作者：
Cao, Ya
LMP1 增强的 kappa 内含子增强子活性有助于通过 NF-kappaB 和 AP-1 通路上调鼻咽癌细胞中 Ig kappa 轻链的表达
影响因子：
37.3
作者：
Liu H;Zheng H;Duan Z;Hu D;Li M;Liu S;Li Z;Deng X;Wang Z;Tang M;Shi Y;Yi W;Cao Y
通讯作者：
Cao Y
影响因子：
9.7
作者：
Mei, YP;Zhu, XF;Zeng, YX
通讯作者：
Zeng, YX
影响因子：
4.8
作者：
Chen, Zhengshan;Gu, Jiang
通讯作者：
Gu, Jiang