How phosphorylation controls p53

The tumor suppressor p53 is a transcription factor that integrates distinct environmental signals including DNA damage, metabolic stress, oncogene activation, hypoxia and virus infection into a common biological outcome that maintains normal cellular control and tissue integrity. p53 is regulated at the post-translational level by protein-protein interactions and covalent modifications, including phosphorylation at over twenty phosphor-acceptor sites. In this perspective we discuss the function of two evolutionarily conserved p53 phosphorylation motifs, located within the N-terminal transactivation and C-terminal regulatory domains, which have recently been shown to play a tumor suppressive role in stem cell niches. We also consider how mechanisms in addition to phosphorylation by stress-activated kinases can lead to the activation of p53 as a transcription factor, and we review the dual role of p53-activating kinases as tumor suppressors and oncoproteins. Finally, we discuss how changes in the specific activity of p53 can have profound effects not only on cancer development but also on organism aging.