mTOR inhibition acts as an unexpected checkpoint in p53-mediated tumor suppression

Here, we showed that the acetylation-defective mice, lacking the ability of cell cycle arrest, senescence, apoptosis, and ferroptosis, were tumor prone but failed to develop early-onset tumors. By identifying a novel p53 acetylation site at lysine K136, we found that simultaneous mutations at all fi...

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Bibliographic Details
Published inGenes & development Vol. 35; no. 1-2; pp. 59 - 64
Main Authors Kon, Ning, Ou, Yang, Wang, Shang-Jui, Li, Huan, Rustgi, Anil K, Gu, Wei
Format Journal Article
LanguageEnglish
Published United States Cold Spring Harbor Laboratory Press 01.01.2021
Subjects
Research Communication
acetylation
tumor suppression
transcriptional regulation
SESN2
Mdm2
mTOR
DDIT4/REDD1
p53
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Summary:Here, we showed that the acetylation-defective mice, lacking the ability of cell cycle arrest, senescence, apoptosis, and ferroptosis, were tumor prone but failed to develop early-onset tumors. By identifying a novel p53 acetylation site at lysine K136, we found that simultaneous mutations at all five acetylation sites (p53-5KR) diminished its remaining tumor suppression function. Moreover, the embryonic lethality caused by the deficiency of was fully rescued in the background of , but not background. p53-4KR retained the ability to suppress mTOR function but this activity was abolished in cells. Notably, the early-onset tumor formation observed in and -null mice was suppressed upon the treatment of the mTOR inhibitor. These results suggest that p53-mediated mTOR regulation plays an important role in both embryonic development and tumor suppression, independent of cell cycle arrest, senescence, apoptosis, and ferroptosis.
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ISSN:0890-9369
1549-5477
DOI:10.1101/gad.340919.120