Phosphorylation of Ser312 contributes to tumor suppression by p53 in vivo.
The tumor suppressor p53 is a master sensor of stress, and posttranslational modifications are key in controlling its stability and transcriptional activities. p53 can be phosphorylated on at least 23 Ser/Thr residues, the majority of which are phosphorylated by stress-related kinases. An exception is Ser315 in human p53 (Ser312 in mouse), which is predominantly phosphorylated by cell cycle-related kinases. To understand the biological importance of Ser312 phosphorylation in vivo, we generated p53Ser312Ala knock-in mice. We show here that, although Ser312 is not essential for mouse life span under normal physiological conditions, Ser312Ala mutation dampens p53's activity during embryonic development. This is evident from its partial rescue of embryonic lethality caused by Mdm4 deletion. In agreement with the notion that Ser312 mutation weakens p53 function, Ser312Ala mice are also more susceptible to tumorigenesis following a sublethal ionizing radiation dose. Importantly, in the cohort studied, Ser312 mutation predisposes mice to develop thymic lymphomas and liver tumors, partly due to p53Ser312Ala's inability to fully induce a set of p53 target genes including p21 and cyclin G1. Thus, we demonstrate that phosphorylation of Ser312 is required for p53 to function fully as a tumor suppressor in vivo.
The Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom.
Elizabeth A
EA
Slee
Barbara
B
Benassi
Robert
R
Goldin
Shan
S
Zhong
Indrika
I
Ratnayaka
Giovanni
G
Blandino
Xin
X
Lu
D000818:Animals; D056766:Cyclin G1 / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D047108:Embryonic Development / Q000235:genetics; D055879:Gene Knock-In Techniques; D008113:Liver Neoplasms / Q000209:etiology; D008223:Lymphoma / Q000209:etiology; D051379:Mice; D020125:Mutation, Missense; D009369:Neoplasms / Q000209:etiology*; D010766:Phosphorylation; D012694:Serine / Q000378:metabolism*; D013953:Thymus Neoplasms / Q000209:etiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D056766:Cyclin G1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; D012694:Serine