Structural basis for gene activation by p53 family members

The p53 tumor suppressor is a modular transcription factor that determines cellular outcome (cell cycle arrest and DNA repair vs. apoptosis) in response to stress signals. The two p53 homologues, p63 and p73 play an important role in development but also act as tumor suppressors. The p53 family members are highly homologous in the activation domain (AD), the DNA-binding domain (DBD) and the tetramerization domain (TD) but differ in the C-terminus. Indeed, the p53 C-terminus contains a basic domain (BD) whereas p63/p73 have a sterile alpha motif (SAM) domain and an inhibitory domain (ID). In addition to the full-length proteins, the p53 family genes produce multiple isoforms truncated at the NH2- and/or C-terminus. Importantly, every functional domain is a determinant in the transactivation of specific target genes by the p53 family members. Distinct post-translational modifications and interactions with cofactors further modulate the transcriptional activity of the p53 family members in response to particular stress signals. Therefore, divergence in the composition of the p53 family proteins is responsible for the diversity of p53 family functions.