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Induction and Validation of Cellular Senescence in Primary Human Cells
08:18

Induction and Validation of Cellular Senescence in Primary Human Cells

Published on: June 20, 2018

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FBXW7 inactivation induces cellular senescence via accumulation of p53

Longyuan Gong1,2,3, Danrui Cui1,2,4, Dian Liu1,2,3

  • 1Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Cell Death & Disease
|September 14, 2022
PubMed

Insights

F-box and WD repeat domain containing 7 (FBXW7) regulates cellular senescence by targeting p53 for degradation. FBXW7 loss induces senescence, which is dependent on p53 status and can be rescued by p53 inactivation.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Oncology

Background:

  • F-box and WD repeat domain containing 7 (FBXW7) is an SCF E3 ubiquitin ligase substrate receptor involved in cell growth, division, and differentiation.
  • The precise role of FBXW7 in regulating cellular senescence has not been fully elucidated.

Purpose of the Study:

  • To investigate the role of FBXW7 in the regulation of cellular senescence.
  • To determine the relationship between FBXW7, p53, and senescence pathways.

Main Methods:

  • FBXW7 inactivation using siRNA and CRISPR/Cas9.
  • Analysis of cellular senescence markers and cell growth.
  • Assessment of p53/p21 and p16INK4a/Rb pathway activation.
  • In vivo studies using a radiation-induced senescence mouse model.

Main Results:

  • FBXW7 inactivation induced cellular senescence in p53 wild-type cells, but not in p53 mutant or null cells.
  • Senescence induction by FBXW7 deficiency was dependent on p53, as p53 inactivation abrogated senescence and cell growth arrest.
  • FBXW7 deletion accelerated replicative senescence and induced the senescence-associated secretory phenotype in a p53-dependent manner.
  • Simultaneous deletion of p53 rescued accelerated senescence and aging in a radiation-induced senescence mouse model.

Conclusions:

  • FBXW7 plays a critical role in regulating cellular senescence through p53 degradation.
  • FBXW7 acts as a tumor suppressor by eliminating p53, thereby preventing premature senescence.
  • Targeting FBXW7 could be a potential therapeutic strategy in cancer, but its role in senescence needs careful consideration.

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