The PDZ ligand domain of the human papillomavirus type 16 E6 protein is required for E6's induction of epithelial hyperplasia in vivo
The PDZ ligand domain of the human papillomavirus type 16 E6 protein is required for E6's induction of epithelial hyperplasia in vivo
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DOI：
10.1128/jvi.77.12.6957-6964.2003
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发表时间：
2003-06-01
影响因子：
5.4
通讯作者：
Lambert, PF
中科院分区：
文献类型：
--
作者：
Nguyen, ML;Nguyen, MM;Lambert, PF
人类乳头瘤病毒(HPV)是尖锐湿疣的病原体。感染高危HPV与肛门癌和头颈癌有关。导致HPV致癌活性的病毒基因之一是E6。在其表皮中表达HPV-16E6蛋白的小鼠(K14E6(WT))会发生上皮增生和鳞癌。许多细胞蛋白与E6相互作用，其中一些可以根据其E6结合区中的共同氨基酸基序进行分组。其中一个基团是PDZ伙伴，包括hDLG、hSCRIBBLE、MUPP1和MAGI，通过它们的PDZ结构域与E6的羧基末端四个氨基酸结合。E6‘S与开发区合作伙伴的互动导致了他们的退化。此外，E6‘S与PDZ蛋白的结合与其在组织培养中转化幼鼠肾脏细胞的能力和在异种移植实验中赋予细胞致瘤性的能力有关。为了解决E6结合PDZ结构域伙伴的能力是否是E6在体内促进上皮过度增殖所必需的，我们建立了在复层鳞状上皮中表达从人角蛋白14(K14)启动子中缺乏最后六个氨基酸的E6(Delta146-151)的转基因小鼠。K14E6(Delta146-151)小鼠表现出与K14E6(WT)小鼠相似的辐射反应，表明该蛋白如预测的那样，保留了灭活P53的能力。而K14E6(Delta146-151)小鼠未见上皮细胞增生。这些结果表明，E6与PDZ伙伴的相互作用是其诱导上皮增生所必需的。
Human papillomaviruses (HPVs) are the causative agent of warts. Infections with high-risk HPVs are associated with anogenital and head and neck cancers. One of the viral genes responsible for HPVs oncogenic activity is E6. Mice expressing the HPV-16 E6 protein in their epidermis (K14E6(WT)) develop epithelial hyperplasia and squamous carcinomas. Numerous cellular proteins interact with E6, some of which can be grouped based on common amino acid motifs in their E6-binding domains. One such group, the PDZ partners, including hDLG, hSCRIBBLE, MUPP1, and MAGI, bind to the carboxy-terminal four amino acids of E6 through their PDZ domains. E6's interaction with the PDZ partners leads to their degradation. Additionally, E6's binding to PDZ proteins has been correlated with its ability to transform baby rat kidney cells in tissue culture and to confer tumorigenicity onto cells in xenograft experiments. To address whether the ability of E6 to bind PDZ domain partners is necessary for E6 to confer epithelial hyperproliferation in vivo, we generated transgenic mice that express in stratified squamous epithelia a mutant of E6 lacking the last six amino acids at its carboxyl terminus, E6(Delta146-151), from the human keratin 14 (K14) promoter. The K14E6(Delta146-151) mice exhibit a radiation response similar to that of the K14E6(WT) mice, demonstrating that this protein, as predicted, retains an ability to inactivate p53. However, the K14E6(Delta146-151) mice fail to display epithelial hyperplasia. These results indicate that an interaction of E6 with PDZ partners is necessary for its induction of epithelial hyperplasia.