From the Department of Basic Medical Sciences, Tsinghua University School of Medicine, Beijing, China 100084 and.
Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
J Biol Chem. 2019 Apr 26;294(17):7037-7045. doi: 10.1074/jbc.RA119.007897. Epub 2019 Mar 11.
Proliferating cell nuclear antigen (PCNA) and its posttranslational modifications regulate DNA metabolic reactions, including DNA replication and repair, at replication forks. PCNA phosphorylation at Tyr-211 (PCNA-Y211p) inhibits DNA mismatch repair and induces misincorporation during DNA synthesis. Here, we describe an unexpected role of PCNA-Y211p in cancer promotion and development. Cells expressing phosphorylation-mimicking PCNA, PCNA-Y211D, show elevated hallmarks specific to the epithelial-mesenchymal transition (EMT), including the up-regulation of the EMT-promoting factor Snail and the down-regulation of EMT-inhibitory factors E-cadherin and GSK3β. The PCNA-Y211D-expressing cells also exhibited active cell migration and underwent G/M arrest. Interestingly, all of these EMT-associated activities required the activation of ATM and Akt kinases, as inactivating these protein kinases by gene knockdown or inhibitors blocked EMT-associated signaling and cell migration. We concluded that PCNA phosphorylation promotes cancer progression via the ATM/Akt/GSK3β/Snail signaling pathway. In conclusion, this study identifies a novel PCNA function and reveals the molecular basis of phosphorylated PCNA-mediated cancer development and progression.
增殖细胞核抗原（PCNA）及其翻译后修饰调节复制叉处的 DNA 代谢反应，包括 DNA 复制和修复。PCNA 在 Tyr-211 位点的磷酸化（PCNA-Y211p）抑制 DNA 错配修复，并在 DNA 合成过程中诱导错误掺入。在这里，我们描述了 PCNA-Y211p 在促进癌症发生和发展中的一个意外作用。表达磷酸化模拟 PCNA（PCNA-Y211D）的细胞表现出上皮-间充质转化（EMT）特有的标志性升高，包括 EMT 促进因子 Snail 的上调和 EMT 抑制因子 E-钙黏蛋白和 GSK3β 的下调。PCNA-Y211D 表达的细胞还表现出活跃的细胞迁移，并经历 G2/M 期阻滞。有趣的是，所有这些 EMT 相关活性都需要 ATM 和 Akt 激酶的激活，因为通过基因敲低或抑制剂失活这些蛋白激酶会阻断 EMT 相关信号和细胞迁移。我们得出结论，PCNA 磷酸化通过 ATM/Akt/GSK3β/Snail 信号通路促进癌症进展。总之，这项研究确定了 PCNA 的一个新功能，并揭示了磷酸化 PCNA 介导的癌症发生和发展的分子基础。
