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Molecular and Cellular Biology, February 2004, p. 976-984, Vol. 24, No. 3
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.3.976-984.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Phosphorylation of Serine 18 Regulates Distinct p53 Functions in Mice

Hayla K. Sluss, Heather Armata, Judy Gallant, and Stephen N. Jones*

Departments of Cell Biology and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01655

Received 25 August 2003/ Returned for modification 23 September 2003/ Accepted 28 October 2003

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 G1 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.

* Corresponding author. Mailing address: Department of Cell Biology, S3-122, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655. Phone: (508) 856-7500. Fax: (508) 856-7510. E-mail: stephen.jones{at}umassmed.edu.

Molecular and Cellular Biology, February 2004, p. 976-984, Vol. 24, No. 3
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.3.976-984.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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