Cdc6 contributes to abrogating the G1 checkpoint under hypoxic conditions in HPV E7 expressing cells.
Cdc6 contributes to abrogating the G1 checkpoint under hypoxic conditions in HPV E7 expressing cells.
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Cdc6 有助于在缺氧条件下废除 HPV E7 表达细胞中的 G1 检查点
DOI：
10.1038/s41598-017-03060-w
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发表时间：
2017-06-07
影响因子：
4.6
通讯作者：
Chen JJ
中科院分区：
文献类型：
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作者：
Chen H;Zhang Q;Qiao L;Fan X;Zhang W;Zhao W;Chen JJ
人乳头瘤病毒(HPV)在宫颈癌的发生中起核心作用，其癌基因E7在这一过程中起着至关重要的作用。我们在这里展示了E7在低氧条件下取消了G1细胞周期检查点，并分析了关键的细胞周期相关蛋白在这一过程中的潜在作用。为了进一步探讨E7绕过低氧诱导的G1期停滞的机制，我们应用蛋白质组学方法和质谱学方法寻找在低氧条件下表达E7的细胞中差异表达的蛋白质。在已鉴定的差异表达蛋白质中，CDC6是一种DNA复制起始因子，当过表达时显示出致癌活性。我们最近证明了CDC6是E7诱导的重新复制所必需的。值得注意的是，我们在此表明，在缺氧条件下，CDC6在E7介导的G1检查点消除中发挥了作用，并且这种作用可能独立于其在DNA复制启动中的作用。这项研究揭示了CDC6在调节细胞周期进程中的一个新功能，并在HPV相关癌症中具有重要意义。
The human papillomavirus (HPV) plays a central role in cervical carcinogenesis and its oncogene E7 is essential in this process. We showed here that E7 abrogated the G1 cell cycle checkpoint under hypoxia and analyzed key cell cycle related proteins for their potential role in this process. To further explore the mechanism by which E7 bypasses hypoxia-induced G1 arrest, we applied a proteomic approach and used mass spectrometry to search for proteins that are differentially expressed in E7 expressing cells under hypoxia. Among differentially expressed proteins identified, Cdc6 is a DNA replication initiation factor and exhibits oncogenic activities when overexpressed. We have recently demonstrated that Cdc6 was required for E7-induced re-replication. Significantly, here we showed that Cdc6 played a role in E7-mediated G1 checkpoint abrogation under hypoxic condition, and the function could possibly be independent from its role in DNA replication initiation. This study uncovered a new function of Cdc6 in regulating cell cycle progression and has important implications in HPV-associated cancers.