AKT induces senescence in human cells via mTORC1 and p53 in the absence of DNA damage: Implications for targeting mTOR during malignancy

Astle, M. V., Hannan, K. M., Ng, P. Y., Lee, R. S., George, A. J., Hsu, A. K., Haupt, Y., Hannan, R. D. and Pearson, R. B. (2012) AKT induces senescence in human cells via mTORC1 and p53 in the absence of DNA damage: Implications for targeting mTOR during malignancy. Oncogene, 31 15: 1949-1962. doi:10.1038/onc.2011.394


Author Astle, M. V.
Hannan, K. M.
Ng, P. Y.
Lee, R. S.
George, A. J.
Hsu, A. K.
Haupt, Y.
Hannan, R. D.
Pearson, R. B.
Title AKT induces senescence in human cells via mTORC1 and p53 in the absence of DNA damage: Implications for targeting mTOR during malignancy
Journal name Oncogene   Check publisher's open access policy
ISSN 0950-9232
1476-5594
Publication date 2012-04-12
Year available 2011
Sub-type Article (original research)
DOI 10.1038/onc.2011.394
Volume 31
Issue 15
Start page 1949
End page 1962
Total pages 14
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Collection year 2012
Language eng
Abstract The phosphatidylinositol 3-kinase (PI3K)/AKT and RAS oncogenic signalling modules are frequently mutated in sporadic human cancer. Although each of these pathways has been shown to play critical roles in driving tumour growth and proliferation, their activation in normal human cells can also promote cell senescence. Although the mechanisms mediating RAS-induced senescence have been well characterised, those controlling PI3K/AKT-induced senescence are poorly understood. Here we show that PI3K/AKT pathway activation in response to phosphatase and tensin homolog (PTEN) knockdown, mutant PI3K, catalytic, α polypeptide (PIK3CA) or activated AKT expression, promotes accumulation of p53 and p21, increases cell size and induces senescence-associated β-galactosidase activity. We demonstrate that AKT-induced senescence is p53-dependent and is characterised by mTORC1-dependent regulation of p53 translation and stabilisation of p53 protein following nucleolar localisation and inactivation of MDM2. The underlying mechanisms of RAS and AKT-induced senescence appear to be distinct, demonstrating that different mediators of senescence may be deregulated during transformation by specific oncogenes. Unlike RAS, AKT promotes rapid proliferative arrest in the absence of a hyperproliferative phase or DNA damage, indicating that inactivation of the senescence response is critical at the early stages of PI3K/AKT-driven tumourigenesis. Furthermore, our data imply that chronic activation of AKT signalling provides selective pressure for the loss of p53 function, consistent with observations that PTEN or PIK3CA mutations are significantly associated with p53 mutation in a number of human tumour types. Importantly, the demonstration that mTORC1 is an essential mediator of AKT-induced senescence raises the possibility that targeting mTORC1 in tumours with activated PI3K/AKT signalling may exert unexpected detrimental effects due to inactivation of a senescence brake on potential cancer-initiating cells.
Keyword PI3K
AKT
Stress
Senescence
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Advance online publication 12 September 2011

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
School of Biomedical Sciences Publications
 
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