INVITRO BIOLOGICAL-ACTIVITIES OF THE E6 AND E7 GENES VARY AMONG HUMAN PAPILLOMAVIRUSES OF DIFFERENT ONCOGENIC POTENTIAL
INVITRO BIOLOGICAL-ACTIVITIES OF THE E6 AND E7 GENES VARY AMONG HUMAN PAPILLOMAVIRUSES OF DIFFERENT ONCOGENIC POTENTIAL
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DOI：
10.1128/jvi.65.1.292-298.1991
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发表时间：
1991-01-01
影响因子：
5.4
通讯作者：
SCHILLER, JT
中科院分区：
文献类型：
--
作者：
BARBOSA, MS;VASS, WC;SCHILLER, JT
人乳头瘤病毒 16 型 (HPV-16) 和 HPV-18 经常在宫颈癌中检测到，而 HPV-6 虽然经常出现在良性生殖器病变中，但很少出现在宫颈癌中。因此，HPV-16和HPV-18感染被认为是高风险，而HPV-6感染被认为是低风险。我们发现，通过使用异源启动子系统，E7 转化蛋白的表达在高危和低危 HPV 之间存在差异。在高危 HPV-16 中，E7 由包含完整上游 E6 开放阅读框的构建体表达。相比之下，HPV-6 E7只有在E6被删除时才能有效翻译。通过使用 HPV-6、HPV-16 和 HPV-18 E7 编码区前面有相同前导序列的克隆，我们发现 E7 基因产物诱导啮齿动物成纤维细胞非贴壁依赖性生长的能力与 HPV 类型的致癌关联直接相关。通过对需要E6和E7互补的正常人角质形成细胞进行永生化测定，我们发现HPV-18的E6和E7都可以互补HPV-16的相应基因。然而，HPV-6的E6和E7都无法替代HPV-16或HPV-18的相应基因。我们的结果表明，在体外检测中，与 HPV-16 和 HPV-18 相比，多种因素，包括 E6 和 E7 较低的内在生物活性以及其表达调节的差异，导致 HPV-6 的活性低于 HPV-16 和 HPV-18。这些相同的因素可能部分解释了这些病毒之间致癌潜力的明显差异。
Human papillomavirus type 16 (HPV-16) and HPV-18 are often detected in cervical carcinomas, while HPV-6, although frequently present in benign genital lesions, is only rarely present in cancers of the cervix. Therefore, infections with HPV-16 and HPV-18 are considered high risk and infection with HPV-6 is considered low risk. We found, by using a heterologous promoter system, that expression of the E7 transforming protein differs between high- and low-risk HPVs. In high-risk HPV-16, E7 is expressed from constructs containing the complete upstream E6 open reading frame. In contrast, HPV-6 E7 was efficiently translated only when E6 was deleted. By using clones in which the coding regions of HPV-6, HPV-16, and HPV-18 E7s were preceded by identical leader sequences, we found that the ability of the E7 gene products to induce anchorage-independent growth in rodent fibroblasts correlated directly with the oncogenic association of the HPV types. By using an immortalization assay of normal human keratinocytes that requires complementation of E6 and E7, we found that both E6 and E7 of HPV-18 could complement the corresponding gene from HPV-16. However, neither E6 nor E7 from HPV-6 was able to substitute for the corresponding gene of HPV-16 or HPV-18. Our results suggest that multiple factors, including lower intrinsic biological activity of E6 and E7 and differences in the regulation of their expression, account for the low activity of HPV-6, in comparison with HPV-16 and HPV-18, in in vitro assays. These same factors may, in part, account for the apparent difference in oncogenic potential between these viruses.