Epstein-Barr virus latent membrane protein 2A upregulates UDP-glucose dehydrogenase gene expression via ERK and PI3K/Akt pathway
Epstein-Barr virus latent membrane protein 2A upregulates UDP-glucose dehydrogenase gene expression via ERK and PI3K/Akt pathway
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DOI：
10.1111/j.1462-5822.2008.01221.x
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发表时间：
2008-12-01
影响因子：
3.4
通讯作者：
Chang, Hwan-You
中科院分区：
文献类型：
--
作者：
Pan, Yun-Ru;Vatsyayan, Jaya;Chang, Hwan-You
EB病毒潜伏膜蛋白2A（LMP 2A）是鼻咽癌（NPC）中常见的高转移性肿瘤。最近的微阵列分析指出，参与糖胺聚糖合成的UDP-葡萄糖脱氢酶（UGDH）基因的表达与NPC活检中的LMP 2A水平高度相关。这项研究扩展了这一发现，并证明了UGDH转录和蛋白质的数量，酶活性，和糖胺聚糖含量增加LMP 2A过表达的人胚肾293（HEK 293）细胞。荧光素酶报告基因测定表明，转录起始点上游630至486 bp的区域对于LMP 2A介导的基因表达至关重要。此外，该区域中的特异性蛋白1（Sp1）结合位点突变降低了UGDH基因的LMP 2A响应性表达。与这些发现相一致，通过用Sp1特异性抑制剂和小干扰RNA（siRNA）处理细胞，LMP 2A的细胞运动性增强减弱。使用信号通路特异性抑制剂，研究表明，参与LMP 2A诱导的UGDH表达的是磷脂酰肌醇3-激酶（PI 3 K）/Akt和细胞外信号调节激酶（ERK），而不是c-Jun N末端激酶（JNK）和p38。本研究为探讨LMP 2A介导UGDH基因激活的分子机制提供了模型。
The Epstein-Barr virus latent membrane protein 2A (LMP2A) is frequently detected in nasopharyngeal carcinoma (NPC), a tumour of high metastatic capacity. A recent microarray assay notes that expression of the UDP-glucose dehydrogenase (UGDH) gene, participating in glycosaminoglycan synthesis, shows high correlation with LMP2A levels in NPC biopsies. This study extends the finding and demonstrates that the UGDH transcript and protein quantities, the enzyme activity, and glycosaminoglycan contents increase in LMP2A overexpressed human embryonic kidney 293 (HEK293) cells. The luciferase reporter gene assay demarcates that a region from 630 to 486 bp upstream of the transcription start is critical for LMP2A-mediated gene expression. Moreover, a specificity protein 1 (Sp1) binding site mutation in this region reduces the LMP2A-responsive expression of the UGDH gene. Consistent with these findings, cell motility enhancement by LMP2A diminishes by treating the cells with Sp1-specific inhibitor and small interference RNA (siRNA). Using a signalling pathway-specific inhibitor, it is revealed that phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK), not c-Jun N-terminal kinase (JNK) and p38, participate in LMP2A-induced UGDH expression. This study provides a model for molecular mechanism participating in LMP2A-mediated UGDH gene activation.