Fig. 1: Two models for p53-dependent cell fate control.

A p53 is kept inactive via MDM2-mediated E3 ligase activity, which itself is inhibited by stress-dependent post-translational modifications (PTMs) to p53. In the absence of MDM2-mediated degradation, p53 protein levels rise and p53 activates transcription of a broad gene network and dictates cell fate. B The “smart” model suggests that differential binding kinetics of p53 to target gene regulatory sequences dictates cell fate decisions by p53. In this model, intrinsic sequence characteristics (DNA sequence, shape) or modulation of p53 protein activity (PTMs, co-factor binding) drive p53-mediated transcription of selective genes controlling distinct cell fates. C The “dumb” model suggests that p53 protein abundance dictates p53-dependent cell fates. In this model, p53 binds to all permissive p53REs and broadly activates all target genes. As p53 protein levels rise, interactions between p53 and cell type and condition-dependent factors ultimately determine cell fates.