Using mice to examine p53 functions in cancer, aging, and longevity

Abstract

The p53 tumor suppressor is a multifaceted transcription factor that responds to a diverse array of stresses that include DNA damage and aberrant oncogene signaling. On activation, p53 prevents the emergence of cancer cells by initiating cell cycle arrest, senescence (terminal cell cycle arrest), or apoptosis. Although its role in assuring longevity by suppressing cancer is well established, recent studies obtained largely from genetically engineered mouse models suggest that p53 may regulate longevity and aging. In some contexts, it appears that altered p53 activity may enhance longevity, and in others, it appears to suppress longevity and accelerate aging phenotypes. Here, we discuss how genetically engineered mouse models have been used to explore antiproliferative functions of p53 in cancer suppression and how mouse models with altered aging phenotypes have shed light on how p53 might influence the aging process.

Figure 1.

p53 responds to DNA damage and activated oncogenes by distinct pathways to prevent genomic instability and cancer. Note that aberrant oncogene signaling may activate a DNA damage response through induction of replicative stress. DNA damage results in activation of p53 through ATM/ATR kinases phosphorylating p53, whereas aberrantly activated oncogenes induce ARF, which sequesters the E3 ubiquitinase MDM2, allowing p53 stabilization. Activated and stabilized p53 induces either apoptosis or transient or permanent cell cycle arrest (senescence). The activated p53 responses prevent the progression (senescence) or promote the elimination (apoptosis) of a nascent cancer cell. It has been hypothesized that these antiproliferative effects of p53 could promote aging through effects on stem and progenitor cell functionality.