Serine 15 phosphorylation stimulates p53 transactivation but does not directly influence interaction with HDM2

TY - JOUR

T1 - Serine 15 phosphorylation stimulates p53 transactivation but does not directly influence interaction with HDM2

AU - Dumaz, Nicolas

AU - Meek, David W.

PY - 1999/12/15

Y1 - 1999/12/15

N2 - 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.

AB - 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.

U2 - 10.1093/emboj/18.24.7002

DO - 10.1093/emboj/18.24.7002

M3 - Article

C2 - 10601022

SN - 0261-4189

VL - 18

SP - 7002

EP - 7010

JO - EMBO Journal

JF - EMBO Journal

IS - 24

ER -