Jiangsu Province Key Laboratory for Molecular and Medicine Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu, PR China.
Cell Signal. 2013 May;25(5):1176-85. doi: 10.1016/j.cellsig.2013.01.017. Epub 2013 Jan 26.
DNA damage activates p53 and its downstream target genes, which further leads to apoptosis or survival either by the cell cycle arrest or by DNA repair. In many tumors, the heat shock protein 27 (Hsp27) is expressed at high levels to provide protection against anticancer drugs. However, the roles of Hsp27 in p53-mediated cellular responses to DNA damage are controversial. Here, we investigated the interplay between the phosphorylation status of Hsp27 and p53 in kidney 293A (HEK293A) cells and found that over-expressing phosphorylated Hsp27 mimics (Hsp27-3D) activated p53/p21 in an ATM-dependent manner. In addition, incubation with doxorubicin (Dox), an anticancer drug, induced Hsp27 phosphorylation in human adenocarcinoma cells (MCF-7). In contrast, inhibition of Hsp27 phosphorylation retarded both p53 induction and p21 accumulation, and led to cell apoptosis. Furthermore, phosphorylated Hsp27 increased p53 nuclear importing and its downstream target gene expression such as p21 and MDM2, while de-phosphorylated Hsp27 impeded this procession. Taken together, our data suggest that Hsp27, in its phosphorylated or de-phosphorylated status, plays different roles in regulating p53 pathway and cell survival.
DNA 损伤激活 p53 及其下游靶基因，进一步通过细胞周期阻滞或 DNA 修复导致细胞凋亡或存活。在许多肿瘤中，热休克蛋白 27（Hsp27）高水平表达，为抗癌药物提供保护。然而，Hsp27 在 p53 介导的细胞对 DNA 损伤的反应中的作用存在争议。在这里，我们研究了 Hsp27 的磷酸化状态与肾 293A（HEK293A）细胞中 p53 之间的相互作用，发现过表达磷酸化 Hsp27 模拟物（Hsp27-3D）以 ATM 依赖的方式激活 p53/p21。此外，用抗癌药物阿霉素（Dox）孵育人腺癌细胞（MCF-7）诱导 Hsp27 磷酸化。相比之下，抑制 Hsp27 磷酸化会延迟 p53 诱导和 p21 积累，并导致细胞凋亡。此外，磷酸化 Hsp27 增加了 p53 的核输入及其下游靶基因的表达，如 p21 和 MDM2，而去磷酸化 Hsp27 则阻碍了这一过程。总之，我们的数据表明，Hsp27 以其磷酸化或去磷酸化状态在调节 p53 通路和细胞存活方面发挥不同的作用。
