Abstract
Cellular stress-induced temporal alterations—i.e., dynamics—are typically exemplified by the dynamics of p53 that serve as a master to determine cell fate. p53 dynamics were initially identified as the variations of p53 protein levels. However, a growing number of studies have shown that p53 dynamics are also manifested in variations in the activity, spatial location, and posttranslational modifications of p53 proteins, as well as the interplay among all p53 dynamical features. These are essential in determining a specific outcome of cell fate. In this review, we discuss the importance of the multifaceted features of p53 dynamics and their roles in the cell fate decision process, as well as their potential applications in p53-based cancer therapy. The review provides new insights into p53 signaling pathways and their potentials in the development of new strategies in p53-based cancer therapy.
Highlights
Cells are constantly bombarded by a variety of endogenous and environmental stress that results in cellular damage
Damage with a dynamic pattern similar to that in response to IR [32]. This finding indicates that p53 can be quickly activated in response to spontaneous DNA damage in cells. This further indicates that the dynamics of p53 protein level as a part of “p53 dynamics” govern cell signaling that mediates cellular responses to both endogenous/spontaneous and exogenous/environmental DNA damage
Monoubiquitinylated p53 is involved in sub-cellular trafficking including nuclear export and mitochondrial translocation, which facilitate mitochondrial p53-activated apoptosis [43]. These findings suggest that mouse double minute 2 (Mdm2)-mediated p53 ubiquitinylation is dynamic in nature
Summary
Cells are constantly bombarded by a variety of endogenous and environmental stress that results in cellular damage. P53 is activated by various types of stimuli This selectively regulates the transcription of p53 target genes that subsequently mediate cellular responses to stress. The observation indicates only p53i.e., dynamics a singlecan cellinduce level can accurately reflect its in governing p53-mediated cellthat signaling, differentatstimuli unique p53 dynamical function in governing p53‐mediated cellThis signaling, different stimuli can induce unique p53 patterns/features in each individual cell. Arrest, whereas prolonged p53 pulses induced by UV are involved in upregulation of pro-apoptotic genes that can lead to apoptosis [17]. This is further supported by a study from the Lahav group [19]. Different patterns of p53 dynamics can be “translated” into different downstream responses and cellular outcomes by the downstream proteins in the p53 signaling pathway
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