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

Abstract

No other protein shows such multiplicity and diversity of functions as tumor suppressor p53 [1, 2]. Initially, role of p53 as the guardian of cellular genome was considered to be providing protection from progression to malignancy. This was mediated by its function as a transcription factor of genes controlling cell cycle and apoptosis [3]. Subsequent studies have identified a large variety of diverse genes regulated by p53. Among them are 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 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 cells reentered cell cycle [5]. This observation prompted authors to postulate use of Mdm2 antagonists in conjunction with chemotherapy to reversibly arrest normal cells, thereby protecting them from 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 mechanism by which p53 converts cell response to ectopic expression of p21 (cell cycle arrest) from senescence to quiescence? In recent studies Demidenko et al., addressed this question and in elegant experiments authors demonstrated paradoxical capabilities of p53, one to suppress cell senescence by inducing quiescence and another, already known, to induce senescence [3]. 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 involvement of mTOR pathway in direction cell undertakes to become either senescent or quiescent is provided in article in current issue of Aging [9] consistent with their prior findings, authors in this article report that induction of cell cycle arrest in 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 process of induction of cells senescence or quiescence primary role of p53 is in arresting cells in cell cycle. However, ongoing cell growth (rRNA synthesis) in arrested cells mediated by mTOR pathway is deciding factor as to whether they undergo senescence (mTOR activation) or quiescence (mTOR inhibition). The factor responsible for apparent paradoxical properties of p53 was dual and separate function of this protein, one arresting cells in cell cycle and another, inhibiting mTOR [7]. Senescent cells are characterized by large cell/nuclear size and flattened morphology, a characteristic feature of growth imbalance. It was shown before that cellular content of RNA (of which 95% is rRNA) in cycling cells is > 10-fold higher than in quiescent cells [10]. In contrast, induction cell cycle arrest associated with senescent phenotype is paralleled by several-fold rise in rRNA abundance [11]. It is also known that mTOR pathway regulates synthesis of ribosomal components including transcription and processing of pre-rRNA, expression of ribosomal proteins and synthesis of 5SRNA [12]. The critical role of mTOR is thus in adjusting ribosome biogenesis and overall protein biosynthetic capacity (cell growth) to signaling through growth factors pathway and coordinating it with rate of cell cycle progression. Within this context cell senescence can be characterized as uncoupling of rate of cell cycle progression and cell growth mediated by mTOR. Of interest is observation that mTOR activity is accelerated in hematopoietic stem cells from old mice compared to young mice prompting authors to suggest that mTOR inhibitors can be used to rejuvenate aging hematopoietic cells [13]. Not disregarded should be a possibility of regulation of cell senescence by p53 via induction of autophagy. Here again diverse paradoxical properties of p53 have been observed, namely induction of autophagy upon activation and expression of this protein above basal level and inhibition of autophagy after its induction to basal level [14]. This paradoxical effect of p53, which on surface appears to be contradictory, was metaphorically compared with two-faced Roman mythology God and named The Janus of [15]. Considering how extensively intertwined are pathways of autophagy, senescence, apoptosis and aging elucidation of mechanisms involved in induction of senescence versus quiescence by p53 is additionally complicated. Inhibition of mTOR while it enhances autophagy and thus is expected to delay senescence may also be lethal to cancer cells [16]. Further studies are needed to resolve how Janus of Autophagy relates to Janus of Cell Senescence or to Janus of Cell Quiescence.