FBXW7 Confers Radiation Survival by Targeting p53 for Degradation
FBXW7 Confers Radiation Survival by Targeting p53 for Degradation
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FBXW7 通过靶向 p53 降解来赋予辐射生存能力。
DOI：
10.1016/j.celrep.2019.12.032
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发表时间：
2020-01-14
期刊：
影响因子：
8.8
通讯作者：
Zhao, Yongchao
中科院分区：
文献类型：
--
作者：
Cui, Danrui;Xiong, Xiufang;Zhao, Yongchao
抑癌基因P53在整合多种应激反应中起着关键作用。因此，P53的水平受到多种泛素连接酶的精确调控。在这项研究中，我们报道了Skp1-CUL1-F-box(SCF)E3连接酶的底物识别成分FBXW7与P53相互作用，并在暴露于电离辐射或依托泊苷后靶向P53的多泛素化和蛋白酶体降解。在机制上，DNA损伤激活ATM使Ser33和Ser37上的P53磷酸化，从而促进FBXW7与SCFFBXW7的结合和随后的P53降解。通过小分子抑制剂或基因敲除/敲除方法使ATM或SCFFBXW7失活，可以不依赖于MDM2的方式延长DNA损伤时的p53蛋白半衰期。在生物学上，FBXW7失活通过稳定p53来诱导细胞周期停滞和凋亡，从而使癌细胞对辐射或依托泊苷敏感。综上所述，我们的研究阐明了FBXW7通过p53靶向在放疗或化疗过程中促进癌细胞存活的机制。
The tumor suppressor p53 plays a critical role in integrating a wide variety of stress responses. Therefore, p53 levels are precisely regulated by multiple ubiquitin ligases. In this study, we report that FBXW7, a substrate recognition component of the SKP1-CUL1-F-box (SCF) E3 ligase, interacts with and targets p53 for polyubiquitination and proteasomal degradation after exposure to ionizing radiation or etoposide. Mechanistically, DNA damage activates ATM to phosphorylate p53 on Ser33 and Ser37, which facilitates the FBXW7 binding and subsequent p53 degradation by SCFFBXW7. Inactivation of ATM or SCFFBXW7 by small molecular inhibitors or genetic knockdown/knockout approaches extends the p53 protein halflife upon DNA damage in an MDM2-independent manner. Biologically, FBXW7 inactivation sensitizes cancer cells to radiation or etoposide by stabilizing p53 to induce cell-cycle arrest and apoptosis. Taken together, our study elucidates a mechanism by which FBXW7 confers cancer cell survival during radiotherapy or chemotherapy via p53 targeting.