Mutation at p53 serine 389 does not rescue the embryonic lethality in mdm2 or mdm4 null mice.
Mdm2 and its homolog Mdm4 inhibit the function of the tumor suppressor p53. Targeted disruption of either mdm2 or mdm4 genes in mice results in embryonic lethality that is completely rescued by concomitant deletion of p53, suggesting that deletion of negative regulators of p53 results in a constitutively active p53. Thus, these mouse models offer a unique in vivo system to assay the functional significance of different p53 modifications. Phosphorylation of serine 389 in murine p53 occurs specifically after ultraviolet-light-induced DNA damage, and phosphorylation of this site enhances p53 activity both in vitro and in vivo. Recently, mice with a serine to alanine substitution at serine 389 (p53S389A) in the endogenous p53 locus were generated. To examine the in vivo significance of serine 389 phosphorylation during embryogenesis, we crossed these mutant mice to mice lacking mdm2 or mdm4. The p53S389A allele did not alter the embryonic lethality of mdm2 or mdm4. Additional crosses to assay the effect of one p53S389A allele with a p53 null allele also did not rescue the lethal phenotypes. In conclusion, the phenotypes due to loss of mdm2 or mdm4 were not even partially rescued by p53S389A, suggesting that p53S389A is functionally wild type during embryogenesis.
Iwakuma
Tomoo
T
Department of Molecular Genetics, Section of Cancer Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Parant
John M
JM
Fasulo
Mark
M
Zwart
Edwin
E
Jacks
Tyler
T
de Vries
Annemieke
A
Lozano
Guillermina
G
D000818:Animals; D005313:Fetal Death / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000172:deficiency* / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2; D012694:Serine; D014158:Transcription, Genetic / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases; D014466:Ultraviolet Rays
C461497:Mdm4 protein, mouse; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D012694:Serine; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases