p53: Good Cop/Bad Cop
Norman E. Sharpless and Ronald A. DePinho
Activation of the p53 transcription factor in response to a variety of cellular stresses, including DNA damage and oncogene activation, initiates a program of gene expression that blocks the proliferative expansion of damaged cells. While the beneficial impact of the anti- cancer function of p53 is well established, several re- cent papers suggest that p53 activation may in some circumstances act in a manner detrimental to the long- term homeostasis of the organism. Here, we discuss the significant participation of p53 in three non-mutu- ally exclusive theories of human aging involving DNA damage, telomere shortening, and oxidative stress. These “good cop/bad cop” functions of p53 appear to place it at the nexus of two opposing forces, cancer and aging. By extension, this relationship implies that therapies aimed to reduce cancer and postpone aging, and thereby increase longevity, will necessarily work either upstream or downstream, but not on the level of, p53.