Simonson Sara J S, Difilippantonio Michael J, Lambert Paul F
McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, Wisconsin 53706, USA.
Cancer Res. 2005 Sep 15;65(18):8266-73. doi: 10.1158/0008-5472.CAN-05-1651.
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(delta146-151) 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(delta146-151) 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(delta146-151) 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.
高危型人乳头瘤病毒，如HPV16，可引发宫颈癌、其他肛门生殖器癌以及一部分头颈癌。E6和E7是在这些癌症中表达的两种病毒癌基因，它们编码的多功能蛋白分别以能够结合并使肿瘤抑制因子p53和pRb失活而闻名。在使用E6转基因（K14E6(WT)）小鼠进行的皮肤癌发生实验中，发现HPV16 E6在皮肤癌发生的两个不同阶段发挥作用：促进阶段，即参与良性乳头瘤形成的步骤；进展阶段，即参与良性肿瘤向恶性癌症转化的步骤。在本研究中，我们比较了K14E6(WT)小鼠与K14E6(delta146 - 151)小鼠的致瘤特性，后者表达一种E6突变体，该突变体无法结合一类被称为PDZ结构域蛋白的细胞蛋白，但仍保留使p53失活的能力。在皮肤癌发生实验中，K14E6(delta146 - 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K14E6(WT)小鼠产生的肿瘤中经常能看到6号染色体的增加，但在K14E6(delta146 - 151)小鼠产生的肿瘤中却很少见。这一观察结果支持了这两种小鼠品系中癌症发展性质不同的前提。基于这些研究，我们得出结论，E6通过破坏多种细胞途径促进癌症发生，其中一条途径是通过其与PDZ结构域伙伴的相互作用介导的，另一条途径是通过E6使p53失活介导的。
