FBXW7 inactivation induces cellular senescence via accumulation of p53.
FBXW7 inactivation induces cellular senescence via accumulation of p53.
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DOI：
10.1038/s41419-022-05229-2
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发表时间：
2022-09-14
影响因子：
9
通讯作者：
Zhao, Yongchao
中科院分区：
文献类型：
--
作者：
Gong, Longyuan;Cui, Danrui;Liu, Dian;Shen, Xiao;Pan, Hui;Xiong, Xiufang;Zhao, Yongchao
FBXW 7是SKP 1-CUL 1-F-box（SCF）E3泛素连接酶的底物受体，在细胞生长、分裂和分化等过程中发挥重要作用，通过靶向不同的关键调控因子进行降解。然而，它在调节细胞衰老中的作用仍然难以捉摸。在这里，我们发现通过基于siRNA的敲除或基于CRISPR/Cas9的敲除的FBXW 7失活在p53野生型细胞中诱导显著的细胞衰老，但在p53突变体或无效细胞中不诱导显著的细胞衰老，沿着p53/p21和p16 INK 4a/Rb途径的激活。同时p53失活废除衰老和FBXW 7缺陷诱导的细胞生长停滞以及p53/p21和p16 INK 4a/Rb途径的改变。此外，Fbxw 7缺失以p53依赖的方式加速原代小鼠胚胎成纤维细胞的复制性衰老。此外，FBXW 7缺失诱导衰老相关的分泌表型触发继发性衰老。重要的是，在辐射诱导的衰老小鼠模型中，同时缺失p53挽救了由Fbxw 7丢失引起的加速衰老和老化。因此，我们的研究揭示了FBXW 7通过消除p53在衰老调节中的新作用。
F-box and WD repeat domain containing 7 (FBXW7) acts as a substrate receptor of SKP1-CUL1-F-box (SCF) E3 ubiquitin ligase and plays crucial roles in the regulation of several cellular processes, including cell growth, division, and differentiation, by targeting diverse key regulators for degradation. However, its role in regulating cellular senescence remains elusive. Here, we found that FBXW7 inactivation by siRNA-based knockdown or CRISPR/Cas9-based knockout induced significant cellular senescence in p53 wild-type cells, but not in p53 mutant or null cells, along with activation of both the p53/p21 and p16INK4a/Rb pathways. Simultaneous p53 inactivation abrogated senescence and cell growth arrest induced by FBXW7 deficiency as well as the alteration of both the p53/p21 and p16INK4a/Rb pathways. Moreover, Fbxw7 deletion accelerated replicative senescence of primary mouse embryonic fibroblasts in a p53-dependent manner. In addition, FBXW7 deletion induced the senescence-associated secretory phenotype to trigger secondary senescence. Importantly, in a radiation-induced senescence mouse model, simultaneous deletion of p53 rescued accelerated senescence and aging caused by Fbxw7 loss. Thus, our study uncovered a novel role for FBXW7 in the regulation of senescence by eliminating p53.
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DOI：
10.1146/annurev-pathol-121808-102144
发表时间：
2010
期刊：
Annual review of pathology
影响因子：
--
作者：
Coppé JP;Desprez PY;Krtolica A;Campisi J
通讯作者：
Campisi J
影响因子：
2.7
作者：
Jandke, Anett;Da Costa, Clive;Behrens, Axel
通讯作者：
Behrens, Axel
影响因子：
21.3
作者：
Campaner, Stefano;Doni, Mirko;Amati, Bruno
通讯作者：
Amati, Bruno
影响因子：
18.2
作者：
Campisi J
通讯作者：
Campisi J
影响因子：
21.3
作者：
Jun, Joon-Il;Lau, Lester F.
通讯作者：
Lau, Lester F.