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Mutation at p53 serine 389 does not rescue the embryonic lethality in mdm2 or mdm4 null mice

Tomoo Iwakuma1, John M Parant, Mark Fasulo

  • 1Department of Molecular Genetics, Section of Cancer Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Oncogene
|September 14, 2004
PubMed

Insights

The tumor suppressor p53 is regulated by Mdm2 and Mdm4. A specific p53 modification, serine 389 phosphorylation, was investigated for its role in embryogenesis but found to be functionally wild type.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • Mdm2 and Mdm4 are negative regulators of the tumor suppressor p53.
  • Loss of Mdm2 or Mdm4 function leads to embryonic lethality, which is rescued by p53 deletion.
  • p53 phosphorylation at serine 389 is induced by DNA damage and enhances p53 activity.

Purpose of the Study:

  • To investigate the in vivo significance of p53 serine 389 phosphorylation during embryogenesis.
  • To determine if p53S389A mutation affects embryonic lethality caused by mdm2 or mdm4 deficiency.

Main Methods:

  • Generation of mice with a serine to alanine substitution at serine 389 in p53 (p53S389A).
  • Crossing p53S389A mutant mice with mdm2- or mdm4-deficient mice.
  • Assaying the effect of p53S389A in combination with a p53 null allele on lethal phenotypes.

Main Results:

  • The p53S389A allele did not rescue the embryonic lethality observed in mdm2 or mdm4 knockout mice.
  • The presence of one p53S389A allele did not rescue the lethal phenotypes when combined with a p53 null allele.

Conclusions:

  • p53 serine 389 phosphorylation is not essential for embryogenesis.
  • The p53S389A mutation is functionally equivalent to wild-type p53 during embryonic development.

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