Another "Janus paradox" of p53: induction of cell senescence versus quiescence

other protein shows such multiplicity and diversity of functions as the tumor suppressor p53 [1,2]. Initially, the role of p53 as " the guardian of the cellular genome " was considered to be providing protection from progression to malignancy. This was mediated by its function as a transcription factor of the genes controlling cell cycle and apoptosis [3]. Subsequent studies have identified a large variety of diverse genes regulated by p53. Among them are the genes modulating cellular senescence, DNA repair, oxidative stress, longevity, angiogenesis, differentiation, glycolysis, tumor motility and invasion, and even bone remodeling [1,2]. Independently of its transcription-regulatory mechanism p53 can also directly interact with proteins of Bcl2 family controlling the execution of apoptotic response [4]. It was recently reported that induction of cell senescence by ectopic expression of p21 and doxorubicin when combined with upregulation of p53 by inhibition of Mdm2, mediated by nutlin-3a, led to cell quiescence. The quiescence was reversible: upon removal of nutlin-3a the cells reentered the cell cycle [5]. This observation prompted the authors to postulate the use of Mdm2 antagonists in conjunction with chemotherapy to reversibly arrest normal cells, thereby protecting them from the drugs targeting cell cycle progression (cyclotherapy) [5]. Consistent with this observation were findings that p53 plays an important role in regulating stem cell quiescence, self-renewal and aging [6]. What is the mechanism by which p53 converts the cell response to the ectopic expression of p21 (cell cycle arrest) from senescence to quiescence? In recent studies Commentary Demidenko et al., addressed this question and in elegant experiments the authors demonstrated the " paradoxical " capabilities of p53, one to suppress cell senescence by inducing quiescence and another, already known, to induce senescence [7]. Suppression of senescence paralleled by induction of quiescence by p53 required its transactivation function, and in analogy to rapamycin, was mediated, at least in part, by inhibition of mTOR pathway [8]. Further evidence on the involvement of mTOR pathway in the direction the cell undertakes to become either senescent or quiescent is provided in the article in the current issue of Aging [9] consistent with their prior findings, the authors in this article report that induction of cell cycle arrest in the WI-38-tert or HT-1080-p21 cells, in which nutlin-3a inhibited mTOR, led to quiescence rather than senescence. In contrast, augmentation of mTOR pathway led to induction of senescence [9]. The data collectively suggest that in the …