Mechanisms of transcriptional regulation by p53

p53 is a transcription factor that suppresses tumor growth through regulation of dozens of target genes with diverse biological functions. The activity of this master transcription factor is inactivated in nearly all tumors, either by mutations in the TP53 locus or by oncogenic events that decrease the activity of the wild-type protein, such as overexpression of the p53 repressor MDM2. However, despite decades of intensive research, our collective understanding of the p53 signaling cascade remains incomplete. In this review, we focus on recent advances in our understanding of mechanisms of p53-dependent transcriptional control as they relate to five key areas: (1) the functionally distinct N-terminal transactivation domains, (2) the diverse regulatory roles of its C-terminal domain, (3) evidence that p53 is solely a direct transcriptional activator, not a direct repressor, (4) the ability of p53 to recognize many of its enhancers across diverse chromatin environments, and (5) mechanisms that modify the p53-dependent transcriptional program in a context-dependent manner.