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.

中文翻译：

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mTOR激酶通过磷酸化p53导致PTEN缺失诱导的细胞衰老。

PTEN（PI3K / AKT途径的主要负调节剂）的丢失会诱导细胞衰老，作为防御肿瘤发生的故障安全机制，称为PTEN丢失诱导的细胞衰老（PICS）。尽管许多研究表明，mTOR途径在细胞衰老中起着至关重要的作用，但对mTORC1和mTORC2在PICS中的确切功能尚不甚了解。在这项研究中，我们表明mTOR充当PI3K / AKT下游和PICS中p53上游的关键中继分子。我们发现PTEN耗竭通过p53-p21信号传导诱导细胞衰老，而不会触发DNA损伤反应。mTOR激酶是mTORC1和mTORC2的主要成分，直接结合p53并使其在丝氨酸15处磷酸化。mTORC1和mTORC2与MDM2竞争，并通过积累细胞周期抑制剂p21来增强p53的稳定性，从而诱导细胞衰老。在PTEN基因敲除小鼠的胚胎成纤维细胞中，PTEN缺乏也会诱导mTORC1和mTORC2与p53而不是MDM2结合，从而导致细胞衰老。这些结果首次共同证明，mTOR通过AKT的促生长活性与p53的抑制生长活性之间的直接联系，在将细胞从增殖信号转为衰老信号中发挥关键作用。