Induction of genomic instability by HPV E6 and E7

人乳头瘤病毒（HPV）感染是宫颈癌发生的必要条件，但不是充分条件。 HPV引起的基因组不稳定性可能使细胞积累必要的额外遗传异常 并在致癌作用中起因果作用。HPV E6的表达和 原代人角质形成细胞（PHK）中的E7癌基因导致多倍性，纺锤体增强了多倍性 破坏和DNA损伤。以前，假设E6和E7通过废除 有丝分裂纺锤体检查点和E6降解肿瘤抑制因子p53以诱导多倍性。我们最近 研究表明E6和E7对纺锤体检查点没有显著影响。而是 废除有丝分裂后检查点以在微管破坏后诱导多倍性。有趣的是，E6突变体 p53降解缺陷也诱导多倍体。此外，我们的研究表明，Cdk 4的重要作用， Cdk 1在E6诱导的多倍体中起重要作用。此外，E7诱导多倍体响应DNA损伤，通过re-DNA修复， DNA复制是一个连续几轮的DNA复制过程，没有中间的有丝分裂。而且我们 发现DNA复制起始因子Cdt 1，其不受控制的表达诱导在细胞中的再复制， 人癌细胞在E7诱导的再复制过程中被后修饰。我们假设 cdk 4和cdk 1的激活在E6对多倍体的p53非依赖性诱导中起重要作用， Cdt 1的修饰是E7诱导再复制所必需的，而E6/E7诱导的多倍性将增强Cdt 1的表达。 发展成非整倍体和癌症。该提案的具体目标旨在测试这些 可能性这些研究将阐明HPV诱导基因组不稳定性的机制， 为药物开发确定目标的承诺。人乳头瘤病毒（HPV）感染可诱导疣，并与疣的发展密切相关。 子宫颈癌HPV癌基因E6和E7对细胞周期检查点的调节有助于HPV-1的形成。 诱导基因组不稳定性。这些研究将揭示HPV诱导癌症的机制， 为确定药物开发的目标提供了希望。

Human papillomavirus (HPV) infection is necessary but not sufficient for the development of cervical cancer. Genomic instability caused by HPV may enable cells to accumulate additional genetic abnormalities necessary for carcinogenesis and has been implicated in a causal role in carcinogenesis. Expression of the HPV E6 and E7 oncogenes in primary human keratinocytes (PHKs) leads to polyploidy, which is enhanced by spindle disruption and DNA damage. Previously, it was hypothesized that E6 and E7 induce polyploidy by abrogating the mitotic spindle checkpoint and that E6 degrades the tumor suppressor p53 to induce polyploidy. Our recent studies demonstrate that E6 and E7 do not have a significant effect on the spindle checkpoint. Instead, they abrogate the postmitotic checkpoint to induce polyploidy after microtubule disruption. Interestingly, E6 mutants defective in p53 degradation also induce polyploidy. Moreover, our studies suggest an important role for Cdk4 and Cdk1 in E6-induced polyploidy. In addition, E7 induces polyploidy in response to DNA damage through re- replication, a process of successive rounds of DNA replication without an intervening mitosis. Furthermore, we find that the DNA replication initiation factor Cdt1, whose uncontrolled expression induces re-replication in human cancer cells, is post-translationally modified during E7-induced re-replication. We hypothesize that activation of cdk4 and cdk1 plays an important role in p53-independent induction of polyploidy by E6, modification of Cdt1 is required for E7 to induce re-replication, and E6/E7-induced polyploidy will enhance the progression into aneuploidy and cancer. The specific aims of the proposal are designed to test these possibilities. These studies will shed light on mechanisms by which HPV induces genomic instability and hold promise for the identification of targets for drug development. Infection with human papillomaviruses (HPV) induces warts and is strongly associated with the development of cervical cancer. Modulation of cell cycle checkpoints by the HPV oncogenes E6 and E7 contributes to HPV- induced genomic instability. These studies will shed light on mechanisms by which HPV induces cancer and hold promise for the identification of targets for drug development.