The expression of matrix metalloproteinase 9 is enhanced by Epstein-Barr virus latent membrane protein 1
The expression of matrix metalloproteinase 9 is enhanced by Epstein-Barr virus latent membrane protein 1
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DOI：
10.1073/pnas.95.7.3621
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发表时间：
1998-03-31
影响因子：
11.1
通讯作者：
Pagano, JS
中科院分区：
文献类型：
--
作者：
Yoshizaki, T;Sato, H;Pagano, JS
基质金属蛋白酶（matrix metalloproteinases，MMPs）在恶性肿瘤细胞中广泛表达，在肿瘤的侵袭和转移中起重要作用。在此，我们报道了MMP 9的表达在EB病毒（EBV）感染的III型潜伏期淋巴瘤细胞系中增加，但在潜伏病毒基因表达高度受限的I型细胞系中不增加。III型细胞系表达丰富的EBV潜伏膜蛋白1（LMP 1），主要的EBV癌蛋白，以及其他潜伏蛋白，包括转录因子，EBV核抗原2，这也是细胞永生化所需要的。在C33 A细胞系中转染LMP 1表达质粒增加MMP 9表达，而过表达EBV核抗原2则没有。与NF-κ B、SP-1和AP-1蛋白的结合位点同源的三个基序有助于通过12-O-十四烷酰基-佛波醇-13-乙酸酯和肿瘤坏死因子cu诱导MMP 9启动子。在这里，我们报告了NF-κ B、SP-1和AP-1的结合位点也有助于病毒蛋白LMP 1对MMP 9启动子的诱导，主要通过NF-κ B，并在较小程度上通过SP-1和AP-1位点。AP-1结合位点的突变可阻断LMP 1对报告基因的诱导作用。共转染I κ B表达质粒可阻断MMP 9表达的增强作用。因此，除了其转化特性，癌蛋白LMP 1可能有助于EBV相关肿瘤如鼻咽癌的侵袭和转移。
Matrix metalloproteinases (MMPs) are frequently expressed in malignant tumor cells and are thought to play crucial roles in tumor invasion and metastasis. Here we report that expression of MMP9 is increased in Epstein-Barr virus (EBV)-infected type III latency lymphoma cell lines, but not in type I lines where latent viral gene expression is highly restricted, Type III cell lines express abundant EBV latent membrane protein 1 (LMP1), the principal EBV oncoprotein, as well as the other latency proteins including the transcriptional factor, EBV nuclear antigen 2, which is also required for cell immortalization. Transfection of an LMP1 expression plasmid in the C33A cell line increased MMP9 expression, whereas overexpression of EBV nuclear antigen 2 did not. Three motifs, homologous to the binding sites of NF-kappa B, SP-1, and AP-1 proteins, contribute to induction of the MMP9 promoter by 12-O-tetradecanoyl-phorbol-13-acetate and tumor necrosis factor cu. Here we report that binding sites for NF-kappa B, SP-1, and AP-1 also contribute to induction of the MMP9 promoter by the viral protein, LMP1, mainly through the NF-kappa B and, to a lesser extent, the SP-1 and AP-1 sites. Moreover the AP-1 binding site is essential in that mutation of it abolished reporter gene induction by LMP1, The enhancement of MMP9 expression was blocked by cotransfection of an I kappa B expression plasmid. Thus in addition to its transforming properties, the oncoprotein LMP1 may contribute to Invasiveness and metastasis of EBV-associated tumors such as nasopharyngeal carcinoma.