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

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

doi:10.1038/s41388-018-0521-8

Seung Hee Jung, Keunwook Lee + Show 8 more

Open Access

https://doi.org/10.1038/s41388-018-0521-8

Copy DOI

Journal: Oncogene	Publication Date: Oct 18, 2018
Citations: 107	License type: open-access

Affiliation: Inha University, Hallym University, Korea University

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.

Highlights

In proliferating cells, various stresses trigger cellular senescence, which acts as a tumor suppression mechanismThese authors contributed : Seung Hee Jung, Hyun Jung HwangElectronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.[1, 2]
As it has been reported that premature senescence is closely correlated with the DNA damage response (DDR) [19, 20], we examined whether DDR is involved in phosphatase and tensin homolog (PTEN)-loss-induced cellular senescence (PICS)
These data indicate that DDR and ROS are not involved in PICS and active AKT-induced senescence

Summary

Introduction

Various stresses trigger cellular senescence, which acts as a tumor suppression mechanism. These authors contributed : Seung Hee Jung, Hyun Jung Hwang. Overexpression of oncogenes (e.g., RAS, BRAF, or MYC) induces cellular senescence (termed oncogeneinduced senescence, or OIS) [3, 4]. Loss of phosphatase and tensin homolog (PTEN), the major negative regulator of the PI3K/AKT pathway, triggers cellular senescence through a p53-dependent pathway called PTEN-loss-induced cellular senescence (PICS) [7, 8]. RAS- and MYC-induced senescence have been well characterized, we do not yet fully understand the mechanisms underlying the cellular senescence induced by PTEN-loss and AKT activation [4, 9]

Methods

Results

Conclusion