ATM-mediated PTEN phosphorylation promotes PTEN nuclear translocation and autophagy in response to DNA-damaging agents in cancer cells
ATM-mediated PTEN phosphorylation promotes PTEN nuclear translocation and autophagy in response to DNA-damaging agents in cancer cells
复制标题
ATM 介导的 PTEN 磷酸化促进 PTEN 核易位和自噬，以响应癌细胞中的 DNA 损伤剂
DOI：
10.1080/15548627.2015.1009767
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发表时间：
2015-02-01
期刊：
影响因子：
13.3
通讯作者：
Zhu, Xiao-Feng
中科院分区：
文献类型：
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作者：
Chen, Jing-Hong;Zhang, Peng;Zhu, Xiao-Feng
PTEN（phosphatase and tensin homolog，磷酸酶和张力蛋白同源物）是一种在人类癌症中经常突变的肿瘤抑制因子，具有多种细胞质和细胞核功能。在氧化应激的作用下，PTEN从细胞质移位到细胞核。然而，易位的机制和功能还不完全清楚。在这项研究中，拓扑异构酶I抑制剂拓扑替康（TPT）和顺铂（CDDP）诱导DNA损伤。结果表明，TPT或CDDP激活ATM（ATM丝氨酸/苏氨酸激酶），ATM在丝氨酸113处磷酸化PTEN，并进一步调节A549和HeLa细胞中的PTEN核转位。核转位后，PTEN诱导自噬，与p-JUN-SESN 2/AMPK通路的激活相关，响应于TPT。这些结果鉴定了ATM对PTEN的磷酸化是PTEN核转位和随后响应于DNA损伤诱导自噬所必需的。
PTEN (phosphatase and tensin homolog), a tumor suppressor frequently mutated in human cancer, has various cytoplasmic and nuclear functions. PTEN translocates to the nucleus from the cytoplasm in response to oxidative stress. However, the mechanism and function of the translocation are not completely understood. In this study, topotecan (TPT), a topoisomerase I inhibitor, and cisplatin (CDDP) were employed to induce DNA damage. The results indicate that TPT or CDDP activates ATM (ATM serine/threonine kinase), which phosphorylates PTEN at serine 113 and further regulates PTEN nuclear translocation in A549 and HeLa cells. After nuclear translocation, PTEN induces autophagy, in association with the activation of the p-JUN-SESN2/AMPK pathway, in response to TPT. These results identify PTEN phosphorylation by ATM as essential for PTEN nuclear translocation and the subsequent induction of autophagy in response to DNA damage.