Dynamics of p53: A Master Decider of Cell Fate

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.

Keywords: p53 dynamics; cell fate decision; cell signaling network.

Figure 1

p53 dynamics in damage response. (A) p53 dynamics can be measured at the levels of frequency, amplitude, and duration; (B) A single prolonged pulses of p53 induced by UV radiation.

Figure 2

p53 dynamics. p53 dynamics include the changes of p53 protein concentration, activity, localization, or modifications that can be measured over time.

Figure 3

Activation of p53 governs the patterns of p53 dynamics. p53 can be activated by DNA double strand breaks (DSBs) induced by IR or single DNA strand breaks (SSBs) induced by UV radiation or nutlin. p53 can be activated by DSBs. This is mediated by the ATM-p53-Wip loop negative feedback loop. Activation of p53 by SSBs is mediated by the ATR-p53-Mdm2 negative feedback loop. These can subsequently lead to a series of transient pulses or a prolonged pulse, which in turn results in cell cycle arrest, cell recovery or apoptosis.

Figure 4

Different dynamic patterns of p53. p53 oscillations (yellow line) that occur at the early stage of DNA damage but with a low amplitude, constitute the basis of p53 dynamic behaviors. Transient p53 pulses (blue line) with a high amplitude occur at the early stage of DNA damage resulting in cell cycle arrest and DNA repair. Sustained p53 pulses (red line) occur at later stages of DNA damage leading to apoptosis.

Figure 5

Posttranslational modifications of p53. (A) p53 can be ubiquitinylated by Mdm2 in mono- and poly-form at a single site and multiple sites. Polyubiquitinylated p53 can bear a polymeric ubiquitin chain with at least four subunits at a single lysine residue. Green dots indicate ubiquitin units; (B) p53 can be phosphorylated at Ser-12/20 facilitating cell cycle arrest. If DNA damage is not repaired, p53 is subsequently phosphorylated at Ser-46 leading to apoptosis. Red dots indicate phosphate groups; (C) p53 can be acetylated and methylated at K373 and K382. Yellow dots indicate acetyl groups, whereas black dots indicate methyl groups. The modifications regulate activation and inactivation of p53.

Figure 6

p53 dynamics in the cell fate decision. Cells under the attack of different types of DNA damage can be directed to different fates. UV-induced DNA SSBs result in a single prolonged pulse of p53 directing cells to the path of irreversible apoptosis. IR-induced DSBs can result in different consequences depending on the extent of DNA damage. In responding to DSBs, cells evaluate the severity of damage repeatedly. If damage is too severe to be repaired, Mdm2 mediates mono-ubiquitinylation of p53 initiating its nuclear export and accumulation in mitochondria. This then initiates the transcription-independent apoptotic program. If DNA damage is repairable, p53 in the nucleus serves as a transcription factor to function in a pulsatile dynamic manner at its protein level. Initially, the p53 protein level exhibits a series of transient pulses, which in turn promote primary modifications of p53 including phosphorylation at Ser-15/20, and acetylation/ demethylation at K373 and K382. These partially activate p53 subsequently transactivating pro-arrest genes and induce cell cycle arrest. Then cells determine whether DNA damage is fixed or not. If it is fixed, p53 returns to its inactive form, and cells survive. If DNA damage cannot be fixed, transient p53 pulses are switched to sustained pulses leading to full activation of p53 through further posttranslational modifications, such as the addition of phosphorylation at Ser-46 and ultimately resulting in apoptosis.