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Phosphorylation of serine 18 regulates distinct p53 functions in mice

Hayla K Sluss1, Heather Armata, Judy Gallant

  • 1Department of Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.

Molecular and Cellular Biology
|January 20, 2004
PubMed

Insights

Phosphorylation of serine 18 in p53 is crucial for apoptosis but not for tumor suppression. This ATM kinase target site specifically regulates p53

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Biology

Background:

  • The p53 protein is a critical tumor suppressor involved in cell cycle arrest and apoptosis.
  • Phosphorylation of serine 15 in human p53 by ATM kinase is proposed to enhance p53 activity.
  • Serine 18 in murine p53 is implicated in ATM-dependent growth arrest.

Purpose of the Study:

  • To investigate the physiological role of serine 18 phosphorylation in murine p53.
  • To determine if serine 18 phosphorylation is essential for p53-mediated apoptosis and tumor suppression.

Main Methods:

  • Generation of mice with a serine-to-alanine mutation at p53 position 18 (p53Ala18).
  • Analysis of apoptosis in thymocytes and splenocytes following DNA damage.
  • Assessment of proliferation in embryonic fibroblasts and G1 arrest.
  • Evaluation of p53 and Mdm2 levels.
  • Observation of tumor development and embryonic lethality in Mdm2-null mice rescue experiments.

Main Results:

  • Phosphorylation of serine 18 is required for robust p53-mediated apoptosis in response to DNA damage.
  • p53 serine 18 phosphorylation did not affect embryonic fibroblast proliferation or G1 arrest.
  • Basal and induced levels of p53 were unaltered by serine 18 phosphorylation.
  • p53Ala18 mice exhibited normal development and no increased susceptibility to spontaneous tumors.
  • Reduced apoptotic function in p53Ala18 did not rescue Mdm2-null embryonic lethality.

Conclusions:

  • Phosphorylation of p53 serine 18 by ATM kinase specifically regulates p53's apoptotic function.
  • Serine 18 phosphorylation is not essential for p53-mediated tumor suppression in mice.
  • The role of serine 18 phosphorylation in p53 function is distinct from its role in tumor suppression.

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