Role of p53 in the Regulation of Cellular Senescence

Abstract

The p53 transcription factor plays a critical role in cellular responses to stress. Its activation in response to DNA damage leads to cell growth arrest, allowing for DNA repair, or directs cellular senescence or apoptosis, thereby maintaining genome integrity. Senescence is a permanent cell-cycle arrest that has a crucial role in aging, and it also represents a robust physiological antitumor response, which counteracts oncogenic insults. In addition, senescent cells can also negatively impact the surrounding tissue microenvironment and the neighboring cells by secreting pro-inflammatory cytokines, ultimately triggering tissue dysfunction and/or unfavorable outcomes. This review focuses on the characteristics of senescence and on the recent advances in the contribution of p53 to cellular senescence. Moreover, we also discuss the p53-mediated regulation of several pathophysiological microenvironments that could be associated with senescence and its development.

Keywords: DNA damage; cell cycle arrest; microenvironment; p53; senescence.

Figure 1

Induction and initiation of cellular growth control and senescence via p53 or P16^INK4A pathways. Various internal or external stress factors trigger the DNA-damage response (DDR) pathway, which in turn activates the p53 and/or the p16^INK4A pathways. p16^INK4A inactivates Cdk4/6, results in accumulation of phosphorylated pRb, stops the regulation of E2F transcription factors, and drives cell cycle arrest or senescence. These stressors also trigger DNA damage (cellular responses to such damages are regulated by either ATM-Chk2 or ATR-Chk1 pathways) and transactivate p53 and p21^CIP1. Moreover, p21^CIP1 protein levels may lead to the inhibition of Cdk4/6 activity, which contribute to the G1 arrest or senescence [33,34].