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Techniques to Induce and Quantify Cellular Senescence
06:51

Techniques to Induce and Quantify Cellular Senescence

Published on: May 1, 2017

35.1K

mTOR kinase leads to PTEN-loss-induced cellular senescence by phosphorylating p53

Seung Hee Jung1,2, Hyun Jung Hwang1,2, Donghee Kang1,2

  • 1Department of Molecular Medicine, College of Medicine, Inha University, Incheon, 22212, Korea.

Oncogene
|October 20, 2018
PubMed

Insights

Loss of PTEN triggers cellular senescence via the mTOR pathway, which directly stabilizes p53 to halt cell growth. This discovery reveals mTOR

Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Biology

Background:

  • PTEN loss is a key driver of tumorigenesis, typically suppressed by PTEN-loss-induced cellular senescence (PICS).
  • The mTOR pathway is implicated in senescence, but its specific roles in PICS, particularly mTORC1 and mTORC2, remain unclear.

Purpose of the Study:

  • To elucidate the precise functions of mTORC1 and mTORC2 in PTEN-loss-induced cellular senescence.
  • To investigate the molecular mechanisms linking PI3K/AKT signaling, mTOR, and p53 in PICS.

Main Methods:

  • Utilized PTEN-depleted cellular models and PTEN-knockout mouse embryonic fibroblasts.
  • Investigated protein-protein interactions and phosphorylation events involving mTOR, p53, and MDM2.
  • Assessed p53 stability and p21 accumulation to determine cell cycle arrest and senescence induction.

Main Results:

  • PTEN depletion induces senescence via p53-p21 signaling independently of DNA damage.
  • mTOR kinase directly binds and phosphorylates p53 at serine 15.
  • mTORC1 and mTORC2 compete with MDM2, stabilizing p53 and promoting senescence through p21 accumulation.

Conclusions:

  • mTOR acts as a crucial mediator between PI3K/AKT signaling and p53 in PICS.
  • mTORC1 and mTORC2 directly regulate p53 stability, driving cellular senescence.
  • This study establishes a novel link between growth-promoting AKT activity and growth-suppressing p53 activity in PICS.

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