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PMID: 14729946 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Phosphorylation of serine 18 regulates distinct p53 functions in mice.

Molecular and cellular biology ·Vol. 24 ·No. 3 ·2004-02-00 ·Pages 976-84

Sluss HK, Armata H, Gallant J, Jones SN

Abstract

The p53 protein acts a tumor suppressor by inducing cell cycle arrest and apoptosis in response to DNA damage or oncogene activation. Recently, it has been proposed that phosphorylation of serine 15 in human p53 by ATM (mutated in ataxia telangiectasia) kinase induces p53 activity by interfering with the Mdm2-p53 complex formation and inhibiting Mdm2-mediated destabilization of p53. Serine 18 in murine p53 has been implicated in mediating an ATM- and ataxia telangiectasia-related kinase-dependent growth arrest. To explore further the physiological significance of phosphorylation of p53 on Ser18, we generated mice bearing a serine-to-alanine mutation in p53. Analysis of apoptosis in thymocytes and splenocytes following DNA damage revealed that phosphorylation of serine 18 was required for robust p53-mediated apoptosis. Surprisingly, p53Ser18 phosphorylation did not alter the proliferation rate of embryonic fibroblasts or the p53-mediated G(1) arrest induced by DNA damage. In addition, endogenous basal levels and DNA damage-induced levels of p53 were not affected by p53Ser18 phosphorylation. p53Ala18 mice developed normally and were not susceptible to spontaneous tumorigenesis, and the reduced apoptotic function of p53Ala18 did not rescue the embryo-lethal phenotype of Mdm2-null mice. These results indicate that phosphorylation of the ATM target site on p53 specifically regulates p53 apoptotic function and further reveal that phosphorylation of p53 serine 18 is not required for p53-mediated tumor suppression.

MeSH Terms
Animals Apoptosis/physiology Fibroblasts/metabolism Mice Nuclear Proteins Phosphorylation Phosphotransferases/metabolism Proto-Oncogene Proteins/genetics,metabolism Proto-Oncogene Proteins c-mdm2 Sequence Analysis, DNA Serine/metabolism Time Factors Tumor Suppressor Protein p53/genetics,metabolism
Chemicals
Nuclear Proteins Proto-Oncogene Proteins Tumor Suppressor Protein p53 Serine Mdm2 protein, mouse Proto-Oncogene Proteins c-mdm2 Phosphotransferases
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Sluss Hayla K
Department of Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
Armata Heather
Gallant Judy
Jones Stephen N
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.24.3.976-984.2004
Published
2004-02-00
Pages
976-84
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC321447
Subset
IM
Grants
NCI NIH HHS · CA-077735 · United States
NCI NIH HHS · R01 CA077735 · United States
NIDDK NIH HHS · P30 DK032520 · United States
NIDDK NIH HHS · 5P30DK32520 · United States
NCI NIH HHS · R56 CA077735 · United States
External Links
PubMed source DOI: 10.1128/MCB.24.3.976-984.2004 PMC Full Text View journal details
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