Serine 312 phosphorylation is dispensable for wild-type p53 functions in vivo

Abstract

Cellular stimulation results in phosphorylation of the tumor suppressor p53 on multiple residues, though the functional relevance is not always clear. It is noteworthy that the serine (S) 315 residue is unique, as it has been suggested to be phosphorylated not only by genotoxic signals, but also during cell-cycle progression and by endoplasmic-reticulum stress. However, in vitro data have been conflicting as phosphorylation at this site was shown to both positively and negatively regulate p53 functions. We have thus generated knock-in mice expressing an unphosphorylable S312 (equivalent to human S315), by substitution with an alanine (A) residue, to clarify the conflicting observations and to evaluate its functional relevance in vivo. Born at Mendelian ratios, the p53 S312A/S312A mice show no anomalies during development and adulthood. p53 activation, stability, localization and ability to induce apoptosis, cell-cycle arrest and prevent centrosome amplification are not compromised in p53 S312A/S312A cells. p53 S312A/S312A mice are unable to rescue mdm2 À/À lethality, and tumorigenesis -both spontaneous and irradiation/oncogene-induced -is not accentuated. Taken together, the results show that the S312 phosphorylation site is not in itself necessary for efficient p53 function, and advocates the possibility that it is neither relevant in the mouse context nor important for p53 functions in vivo.

Mutant TP53 Posttranslational Modifications: Challenges and Opportunities

“…Two mouse models based on TP53 Ser312Ala (corresponding to human TP53 Ser315) have been created in different backgrounds [Slee et al., ; Lee et al., ]. These mice developed normally and remained tumor free for at least 2 years [Slee et al., ; Lee et al., ].…”

p63 the guardian of human reproduction

“…1). 70 - 72 This tight control of p63 is necessary for the crucial function that TAp63 exerts in controlling oocyte death. TAp63, indeed, is phosphorylated and activated following DNA double-strand breaks (DSBs), induced by ionized radiation or cisplatin treatment 73 .…”

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.…”