It Takes 15 to Tango: Making Sense of the Many Ubiquitin Ligases of p53

The transcription factor p53 regulates numerous cellular processes to guard against tumorigenesis. Cell-cycle inhibition, apoptosis, and autophagy are all regulated by p53 in a cell- and context-specific manner, underscoring the need for p53 activity to be kept low in most circumstances. p53 is kept in check primarily through its regulated ubiquitination and degradation by a number of different factors, whose contributions may reflect complex context-specific needs to restrain p53 activity. Chief among these E3 ubiquitin ligases in p53 homeostasis is the ubiquitously expressed proto-oncogene MDM2, whose loss renders vertebrates unable to limit p53 activity, resulting in early embryonic lethality. MDM2 has been validated as a critical, universal E3 ubiquitin ligase for p53 in numerous tissues and organisms to date, but additional E3 ligases have also been identified for p53 whose contribution to p53 activity is unclear. In this review, we summarize the recent advances in our knowledge regarding how p53 activity is apparently controlled by a multitude of ubiquitin ligases beyond MDM2.