2. Academic Validation
  3. FBXW7 inactivation induces cellular senescence via accumulation of p53

FBXW7 inactivation induces cellular senescence via accumulation of p53

  • Cell Death Dis. 2022 Sep 14;13(9):788. doi: 10.1038/s41419-022-05229-2.
Longyuan Gong  # 1 2 3,  Danrui Cui  # 1 2 4,  Dian Liu  # 1 2 3,  Xiao Shen 3,  Hui Pan 5,  Xiufang Xiong 6 7,  Yongchao Zhao 8 9 10 11
Affiliations

Affiliations

  • 1 Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 2 Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 3 Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
  • 4 Cancer Center, Zhejiang University, Hangzhou, China.
  • 5 Department of Lung Transplantation, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 6 Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China. xiufang@zju.edu.cn.
  • 7 Cancer Institute of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. xiufang@zju.edu.cn.
  • 8 Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. yongchao@zju.edu.cn.
  • 9 Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. yongchao@zju.edu.cn.
  • 10 Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China. yongchao@zju.edu.cn.
  • 11 Cancer Center, Zhejiang University, Hangzhou, China. yongchao@zju.edu.cn.
  • # Contributed equally.
PMID: 36104351 DOI: 10.1038/s41419-022-05229-2
Abstract

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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