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首页> 外文期刊>Cellular Signalling >Phosphorylated Hsp27 activates ATM-dependent p53 signaling and mediates the resistance of MCF-7 cells to doxorubicin-induced apoptosis
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Phosphorylated Hsp27 activates ATM-dependent p53 signaling and mediates the resistance of MCF-7 cells to doxorubicin-induced apoptosis

机译:磷酸化的Hsp27激活ATM依赖的p53信号,并介导MCF-7细胞对阿霉素诱导的细胞凋亡的抗性

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摘要

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.
机译:DNA损伤会激活p53及其下游靶基因,进而通过细胞周期停滞或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)以高水平表达,以提供抗癌药物的保护。然而,Hsp27在p53介导的细胞对DNA损伤的反应中的作用是有争议的。在这里,我们调查了肾脏293A(HEK293A)细胞中Hsp27和p53的磷酸化状态之间的相互作用,发现过表达的磷酸化Hsp27模拟物(Hsp27-3D)以ATM依赖性方式激活了p53 / p21。此外,与抗癌药阿霉素(Dox)一起孵育可诱导人腺癌细胞(MCF-7)中的Hsp27磷酸化。相反,抑制Hsp27磷酸化既延迟了p53的诱导,又延迟了p21的积累,并导致细胞凋亡。此外,磷酸化的Hsp27增加了p53核的进口及其下游靶基因表达,如p21和MDM2,而磷酸化的Hsp27则阻止了这一进程。综上所述,我们的数据表明,Hsp27处于磷酸化或去磷酸化状态,在调节p53途径和细胞存活中发挥不同的作用。

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