The Transactivation Domains of the p53 Protein

The p53 tumor suppressor is a transcriptional activator, with discrete domains that participate in sequence-specific DNA binding, tetramerization, and transcriptional activation. Mutagenesis and reporter studies have delineated two distinct activation domains (TADs) and specific hydrophobic residues within these TADs that are critical for their function. Knockin mice expressing p53 mutants with alterations in either or both of the two TADs have revealed that TAD1 is critical for responses to acute DNA damage, whereas both TAD1 and TAD2 participate in tumor suppression. Biochemical and structural studies have identified factors that bind either or both TADs, including general transcription factors (GTFs), chromatin modifiers, and negative regulators, helping to elaborate a model through which p53 activates transcription. Posttranslational modifications (PTMs) of the p53 TADs through phosphorylation also regulate TAD activity. Together, these studies on p53 TADs provide great insight into how p53 serves as a tumor suppressor.