Phosphorylation of Ser312 contributes to tumor suppression by p53 in vivo

Abstract

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 cyclerelated 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.Mdm4 | lymphoma | liver | knock-in | mouse

Transcriptional and Translational Regulation of C/EBPβ-HDAC1 Protein Complexes Controls Different Levels of p53, SIRT1, and PGC1α Proteins at the Early and Late Stages of Liver Cancer

“…We focused our studies on three main targets of the C/EBP␤-HDAC1 complexes: p53, SIRT1, and PGC1␣, and on consequences of the down-regulation of p53 at late stages of liver cancer. It has been shown that the p53-p21 pathway inhibits liver proliferation and that it is eliminated during development of liver cancer (23,24). However, the mechanism of this elimination has not been shown.…”

In the right place at the right time: Analysis of p53 serine 312 phosphorylation in vivo

“…5,6 This residue is phosphorylated by kinases such as cdk2, However when p53 Ser312Ala mice were exposed to a DNA damaging stimulus, opposing results were obtained. Both studies exposed the mice to a single 4 Gy dose of radiation and monitored the mice for tumor development.…”

p53: Point Mutations, SNPs and Cancer

“…This mutation did not affect the survival of mice under normal physiological conditions and appeared to have only mild effects on stress-responses in fibroblasts. However, the irradiation of p53 S312A/S312A mice revealed their predisposition to develop thymic lymphomas and liver tumors, and a decreased p53 response was demonstrated in liver tumors (Slee et al, 2010). As for serine 392, in vitro studies revealed its phosphorylation in response to UV irradiation, correlated with p53 activation (Kapoor and Lozano, 1998;Lu et al, 1998).…”

“…Furthermore, whether this phosphorylation regulates p53 functions positively or negatively appeared controversial after in vitro studies (Fogal et al, 2005;Qu et al, 2004;Zacchi et al, 2002;Zheng et al, 2002). Two mouse models expressing p53 S312A (equivalent to a S315A mutation in human p53) were recently reported (Lee et al, 2010;Slee et al, 2010). This mutation did not affect the survival of mice under normal physiological conditions and appeared to have only mild effects on stress-responses in fibroblasts.…”