Paradoxical suppression of cellular senescence by p53

Abstract

The tumor suppressor p53 is a canonical inducer of cellular senescence (irreversible loss of proliferative potential and senescent morphology). p53 can also cause reversible arrest without senescent morphology, which has usually been interpreted as failure of p53 to induce senescence. Here we demonstrate that p53-induced quiescence actually results from suppression of senescence by p53. In previous studies, suppression of senescence by p53 was masked by p53-induced cell cycle arrest. Here, we separated these two activities by inducing senescence through overexpression of p21 and then testing the effect of p53 on senescence. We found that in p21-arrested cells, p53 converted senescence into quiescence. Suppression of senescence by p53 required its transactivation function. Like rapamycin, which is known to suppress senescence, p53 inhibited the mTOR pathway. We suggest that, while inducing cell cycle arrest, p53 may simultaneously suppress the senescence program, thus causing quiescence and that suppression of senescence and induction of cell cycle arrest are distinct functions of p53. Thus, in spite of its ability to induce cell cycle arrest, p53 can act as a suppressor of cellular senescence.nduction of p53 can cause apoptosis, reversible cell cycle arrest, and cellular senescence (1-5). In contrast to reversible cell cycle arrest (quiescence), cellular senescence is defined by irreversible loss of proliferative potential, acquisition of characteristic morphology (large, flattened cells), and expression of specific biomarkers (e.g., senescence-associated β-galactosidase, SA-β-Gal) (6). Since p53 appeared to induce senescence in some situations, observations of p53-induced quiescence have usually been interpreted as failure of p53 to activate the senescence program, which remains poorly understood. We recently reported that in two cell lines in which ectopic expression of p21 caused senescence, activation of endogenous p21 by endogenous p53 caused quiescence (7). The simplest conventional explanation for this result is that p53 failed to activate p21 to the degree required for induction of senescence, although it was sufficient for induction of quiescence. However, an alternative possibility is that p53 acts as a suppressor of the senescence program. This model leads to the testable prediction that induction of p53 would suppress p21-mediated senescence and convert it into quiescence. Here we demonstrate that this model is indeed correct, which indicates that, despite its ability to induce cell cycle arrest, p53 is a suppressor, not an inducer, of cellular senescence. Retrospectively, this result is not completely unexpected. First, it is known that p53 inhibits the mTOR (mammalian target of rapamycin) pathway (8-12). Second, it is known that inhibition of mTOR by rapamycin converts senescence into quiescence (13-15). In turn, this predicts that p53, like rapamycin, may suppress senescence. Here we confirmed this prediction. ResultsThe p53 Activator Nutlin-3a Suppresses p21-Induced Senescence. As previously show...

Resistance to discodermolide, a microtubule-stabilizing agent and senescence inducer, is 4E-BP1–dependent

“…Previous studies have shown that 4E-BP1 can modulate expression of p21 and HDM2 independently of p53 transcriptional regulation (29,30). An alternative explanation to rationalize the survival of AD32 cells with high expression of p53 may be that p53 acts as a repressor of senescence, as has been recently proposed in a p21-driven model system (31). In another study, it was shown that p53 can repress the senescence-associated secretory phenotype and that ablation of p53 function actually accelerates ACS (24).…”

Aging hair follicles rejuvenated by transplantation to a young subcutaneous environment

“…23 TP53 can convert CDKN1A (p21 CIP1 )-induced irreversible senescence into reversible quiescence possibly by inhibiting the mechanistic target of rapamycin (MTOR). 24,25 High doses of doxorubicin and nutlin-3a, an inhibitor of the interaction between TP53 and its major negative regulator HDM2, promoted reversible quiescence, instead of irreversible senescence. 25,26 MTOR inhibitors, such as rapamycin, may be able to rejuvenate stem cells within the aging hair follicle, as well as restore the responsiveness of the aging stem cells to stimuli.…”

The STAT3-IGFBP5 axis is critical for IL-6/gp130-induced premature senescence in human fibroblasts

“…[37][38][39][40][41] Therefore, in addition to the critical role of the STAT3-IGFBP5 axis in the IL-6-induced premature senescence, mTOR activity caused by serum growth factors and added IL-6 together with secreted factors during the course is likely to contribute to the premature senescence. However, our preliminary experiments showed that TIG3 cells with a chimeric receptor with truncated gp130 containing only the YRHQ motif, which activates only the STAT3 pathway without activating the ERK1/2 or PI3K/AKT/mTOR pathways, induced premature senescence in TIG3 cells at the extent comparable with that shown in IL-6/sIL-6R stimulation (unpublished data, Kojima H and Nakajima K).…”