Be quiet and you'll keep young: does mTOR underlie p53 action in protecting against senescence by favoring quiescence?

a multi-step process that involves abrogation of several barriers to uncontrolled proliferation [1]. These barriers include checkpoints that, by activating inhibitory pathways, block cell division either reversibly (quiescence) or irreversibly (senescence, apoptosis). Typically, confluence and the absence of mitogens or nutrients induce quiescence, while cell ageing, inappropriate signaling or irreparable DNA damage lead to senescence, which is characterized by a large and flat cell morphology and expression of specific biomarkers. Cell cycle arrest requires inhibition of cyclin-dependent kinases (CDK), that drive division by both activating diverse regulators involved in replication and mitosis and by inactivating pRb pocket protein family members. While pocket proteins are essential for both quiescence and senescence [2], p53, another tumor suppressor, has been thought to play a key role in senescence, mainly by inducing the CDK inhibitor p21 Waf1,Cip1,Sdi1 (p21), which permanently blocks cell cycle progression [3]. On the other hand, although clearly involved [4], the role of p53 in quiescence is probably not essential, as this cell cycle arrest is mostly mediated by p27 Kip1 (p27), a CDK inhibitor whose levels are not controlled by p53 [5]. Consistent with this, both serum deprivation and confluence could efficiently induce quiescence in human fibroblasts expressing the HPV16-E6 viral oncogene, which degrades p53 [6]. The straightforward role p53 in senescence has recently been challenged by Blagosklonny and colleagues, who propose that p53 is primarily a suppressor of the senescent phenotype rather than its " inducer " [7]. In Commentary agreement with growing evidence that p53 is involved in cell metabolism [4], they suggest that its another function would be to inhibit mTOR-dependent cell growth in size, thus inducing quiescence by precluding the onset of senescence. Consequently, senescence would occur in situations when the conditions for quiescence are not met and when p53 fails to suppress the mTOR pathway. This exciting but rather heretic hypothesis was based on initial observations showing that senescent phenotype requires cell growth [8, 9] and that, unlike ectopic p21 expression or DNA damage by doxorubicin, p53 induction caused quiescence instead of senescence in some cells [10]. By ingeniously using a cell line in which p21 is expressed from an inducible promoter and Nutlin-3A, an Mdm2 inhibitor and potent p53 stabilizer, they showed that over-expression or stabilization of p53, prevented p21-induced senescence and instead caused quiescence. Moreover, p53 induction could " convert " p21-or oxidative stress-induced senescence into quiescence. The principal target of p53 in …