The choice between p53-induced senescence and quiescence is determined in part by the mTOR pathway

Abstract

Transient induction of p53 can cause reversible quiescence and irreversible senescence. Using nutlin-3a (a small molecule that activates p53 without causing DNA damage), we have previously identified cell lines in which nutlin-3a caused quiescence. Importantly, nutlin-3a caused quiescence by actively suppressing the senescence program (while still causing cell cycle arrest). Noteworthy, in these cells nutlin-3a inhibited the mTOR (mammalian Target of Rapamycin) pathway, which is known to be involved in the senescence program. Here we showed that shRNA-mediated knockdown of TSC2, a negative regulator of mTOR, partially converted quiescence into senescence in these nutlin-arrested cells. In accord, in melanoma cell lines and mouse embryo fibroblasts, which easily undergo senescence in response to p53 activation, nutlin-3a failed to inhibit mTOR. In these senescence-prone cells, the mTOR inhibitor rapamycin converted nutlin-3a-induced senescence into quiescence. We conclude that status of the mTOR pathway can determine, at least in part, the choice between senescence and quiescence in p53-arrested cells.

p53 expression controls prostate cancer sensitivity to chemotherapy and the MDM2 inhibitor Nutlin-3

“…To determine the sensitivities of each cell line with different TP53 statuses to common anticancer drugs used in the treatment of prostate cancer, MTT assays were an increase/decrease in cell cycle regulating and apoptotic proteins needed for the correction of cell damage, cell death or the induction of cellular senescence. 6,[17][18][19][20][21][22] Inhibition of one or more of these controlled processes could result in systematic deregulation within the cell, causing abnormal cell cycle progression, chromosome instability or anti-apoptotic effects. 23,24 The function of p53 as a master regulator in the cell cycle and its role in cancer development is well-documented.…”

“…To do this, we turned to the use of a MDM2-specific inhibitor, Nutlin-3. 3,7,[20][21][22][50][51][52] LNCaP cells express two wild-type TP53 alleles and demonstrated the most significant cellular response to alterations in p53 signaling when mutant DN p53DD was introduced. Therefore, we next performed MTT analysis with LNCaP cells treated with a constant concentration of Nutlin-3 performed.…”

A set of miRNAs participates in the cellular senescence program in human diploid fibroblasts

“…The mammalian target of rapamycin (mTOR) pathway was demonstrated to drive senescence in cells treated with several factors, including oxidative agents. [20][21][22] Thus, initially, we asked whether miRNA transfection caused any change in mTOR pathway activation, by measuring the phosphorylation of the ribosomal S6 protein (S6); S6 is phosphorylated by p70-S6 kinase (p70S6K), which, in turn, is activated by mTOR. 23 IMR90 cells featured high levels of S6 phosphorylation, and adoptive overexpression of any of the five miRNAs (miR-210, miR-376a*, miR-486-5p, miR-494, and miR-542-5p) did not cause detectable change in the levels of phospho-S6 (Supplementary Figure 3).…”

Morphological, molecular and functional differences of adult bone marrow- and adipose-derived stem cells isolated from rats of different ages

“…This casts doubt upon the role of p53 in the senescence programme and indicates that it may suppress senescence by converting the response to quiescence [21]. Upregulation of p53 leads to cell cycle arrest and, as a conse-quence, to the initial step of cellular senescence [22]. In the aging process of an organism, p53 signalling seems to decline as the efficiency of p53-mediated responses to cellular stresses decreases during aging [23].…”