Serine15 phosphorylation stimulates p53 transactivation but does not directly influence interaction with HDM2

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Abstract
The p53 tumour suppressor protein is a labile transcription factor that is activated and stabilized in response to a wide range of cellular stresses, through a mechanism involving disruption of its interaction with MDM2, a negative regulatory partner. Induction of p53 by DNA damage additionally involves a series of phosphorylation and acetylation modifications, some of which are thought to regulate MDM2 binding. Here we report the effects of introducing mutations at several known or putative N‐terminal phosphorylation sites on the transactivation function of p53. These studies highlight phosphorylation of Ser15, a key phosphorylation target during the p53 activation process, as being critical for p53‐dependent transactivation. Biochemical data indicate that the mechanism by which phosphorylation of Ser15 stimulates p53‐dependent transactivation occurs through increased binding to the p300 coactivator protein. The data also indicate that Ser15‐dependent regulation of transactivation is independent of any involvement in modulating MDM2 binding, and that Ser15 phosphorylation alone is not sufficient to block the p53–MDM2 interaction.