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

Seung Hee Jung, Hyun Jung Hwang, Donghee Kang, Hyun A. Park, Hyung Chul Lee, Daecheol Jeong, Keunwook Lee, Heon Joo Park, Young Gyu Ko, Jae Seon Lee

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Loss of PTEN, the major negative regulator of the PI3K/AKT pathway induces a cellular senescence as a failsafe mechanism to defend against tumorigenesis, which is called PTEN-loss-induced cellular senescence (PICS). Although many studies have indicated that the mTOR pathway plays a critical role in cellular senescence, the exact functions of mTORC1 and mTORC2 in PICS are not well understood. In this study, we show that mTOR acts as a critical relay molecule downstream of PI3K/AKT and upstream of p53 in PICS. We found that PTEN depletion induces cellular senescence via p53-p21 signaling without triggering DNA damage response. mTOR kinase, a major component of mTORC1 and mTORC2, directly binds p53 and phosphorylates it at serine 15. mTORC1 and mTORC2 compete with MDM2 and increase the stability of p53 to induce cellular senescence via accumulation of the cell cycle inhibitor, p21. In embryonic fibroblasts of PTEN-knockout mice, PTEN deficiency also induces mTORC1 and mTORC2 to bind to p53 instead of MDM2, leading to cellular senescence. These results collectively demonstrate for the first time that mTOR plays a critical role in switching cells from proliferation signaling to senescence signaling via a direct link between the growth-promoting activity of AKT and the growth-suppressing activity of p53.

Original languageEnglish
Pages (from-to)1639-1650
Number of pages12
JournalOncogene
Volume38
Issue number10
DOIs
Publication statusPublished - 2019 Mar 7

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Jung, S. H., Hwang, H. J., Kang, D., Park, H. A., Lee, H. C., Jeong, D., Lee, K., Park, H. J., Ko, Y. G., & Lee, J. S. (2019). mTOR kinase leads to PTEN-loss-induced cellular senescence by phosphorylating p53. Oncogene, 38(10), 1639-1650. https://doi.org/10.1038/s41388-018-0521-8