Lessons from p53 in non-mammalian models

p53 is a fundamental determinant of oncogenesis, aging physiology and neurodegenerative pathologies. The complexity of the p53 regulatory network can hinder attempts to fully understand how this oncogenic protein operates within/ between cells to constrain growth potential. Orthologs of p53 in non-mammalian models, such as zebrafish, Drosophila and Caenorhabditis elegans, afford simpler models that illuminate core properties of this ancient network. The existence of p53 in short-lived organisms, where cancers do not occur, argues that tumor suppression per se was not the evolutionary pressure shaping p53. Instead, p53 as a constraint against tumor growth was probably co-opted from more ancestral, nonautonomous functions that are entirely unknown. Describing these functional properties will be essential for a comprehensive picture of the p53 regulatory network in normal and disease states. The tractable systems described here offer sophisticated genetic tools and fundamental insights that will continue to be indispensable models for achieving this goal.