Two distinct activities contribute to human papillomavirus 16 E6's oncogenic potential
Two distinct activities contribute to human papillomavirus 16 E6's oncogenic potential
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DOI：
10.1158/0008-5472.can-05-1651
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发表时间：
2005-09-15
期刊：
影响因子：
11.2
通讯作者：
Lambert, PF
中科院分区：
文献类型：
--
作者：
Simonson, SJS;Difilippantonio, MJ;Lambert, PF
高风险的人乳头瘤病毒，如HPV 16，会导致宫颈癌，其他肛门生殖器癌和一部分头颈癌。E6和E7是在这些癌症中表达的两种病毒癌基因，编码多功能蛋白质，其以分别结合和抑制肿瘤抑制因子p53和pRb的能力而闻名。在使用E6转基因（K14 E6（WT））小鼠的皮肤致癌实验中，发现HPV 16 E6促成皮肤致癌的两个不同阶段：促进，涉及良性乳头状瘤形成的步骤，和进展，涉及良性肿瘤恶性转化为坦率癌症的步骤。在这项研究中，我们比较了K14 E6（WT）小鼠与K14 E6（Delta 146-151）小鼠的致瘤特性，后者表达E6的突变形式，不能结合称为PDZ结构域蛋白的细胞蛋白家族，但保留了抑制p53的能力。在皮肤癌发生实验中，K14 E6（Delta 146-151）转基因未能促进皮肤癌发生的促进阶段，但保留了促进进展阶段的能力。细胞遗传学分析表明，尽管在K14 E6（WT）小鼠产生的肿瘤中始终观察到6号染色体的增加，但在K14 E6（Delta 146-151）小鼠产生的肿瘤中很少见到。这一观察结果支持了这两种小鼠品系中癌症发展的性质不同的前提。基于这些研究，我们得出结论，E6有助于癌症通过其破坏多种细胞途径，其中之一是通过其与PDZ结构域的合作伙伴和其他通过E6的p53的失活的相互作用介导。
High-risk human papillomaviruses, such as HPV16, cause cervical cancers, other anogenital cancers, and a subset of head and neck cancers. E6 and E7, two viral oncogenes expressed in these cancers, encode multifunctional proteins best known for their ability to bind and inactivate the tumor suppressors p53 and pRb, respectively. In skin carcinogenesis experiments using E6 transgenic (K14E6(WT)) mice, HPV16 E6 was found to contribute to two distinct stages in skin carcinogenesis: promotion, a step involved in the formation of benign papillomas, and progression, the step involved in the malignant conversion of benign tumors to frank cancer. In this study, we compared the tumorigenic properties of K14E6(WT) mice with those of K14E6(Delta 146-151) mice, which express a mutant form of E6 that cannot bind a family of cellular proteins known as PDZ domain proteins but retains the ability to inactivate p53. In skin carcinogenesis experiments, the K14E6(Delta 146-151) transgene failed to contribute to the promotion stage of skin carcinogenesis but retained the ability to contribute to the progression stage. Cytogenetic analysis indicated that, although gains of chromosome 6 are consistently seen in tumors arising on K14E6(WT) mice, they are infrequently seen in tumors arising on K14E6(Delta 146-151) mice. This observation supports the premise that the nature of cancer development in these two mouse strains is distinct. Based on these studies, we conclude that E6 contributes to cancer through its disruption of multiple cellular pathways, one of which is mediated through its interaction with PDZ domain partners and the other through E6's inactivation of p53.