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Targeted inactivation of Mdm2 RING finger E3 ubiquitin ligase activity in the mouse reveals mechanistic insights into p53 regulation.

Cancer cell | Oct 15, 2007

It is believed that Mdm2 suppresses p53 in two ways: transcriptional inhibition by direct binding, and degradation via its E3 ligase activity. To study these functions physiologically, we generated mice bearing a single-residue substitution (C462A) abolishing the E3 function without affecting p53 binding. Unexpectedly, homozygous mutant mice died before E7.5, and deletion of p53 rescued the lethality. Furthermore, reintroducing a switchable p53 by crossing with p53ER(TAM) mice surprisingly demonstrated that the mutant Mdm2(C462A) was rapidly degraded in a manner indistinguishable from that of the wild-type Mdm2. Hence, our data indicate that (1) the Mdm2-p53 physical interaction, without Mdm2-mediated p53 ubiquitination, cannot control p53 activity sufficiently to allow early mouse embryonic development, and (2) Mdm2's E3 function is not required for Mdm2 degradation.

Pubmed ID: 17936560 RIS Download

Mesh terms: Amino Acid Substitution | Animals | Cells, Cultured | DNA Damage | Down-Regulation | Embryo, Mammalian | Fibroblasts | Gamma Rays | Gene Expression Regulation, Developmental | Genotype | Gestational Age | Homozygote | Mice | Mice, Inbred C57BL | Mice, Knockout | Mutagenesis, Site-Directed | Mutation | Phenotype | Proteasome Endopeptidase Complex | Protein Structure, Tertiary | Proto-Oncogene Proteins c-mdm2 | Transcription, Genetic | Tumor Suppressor Protein p53

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Associated grants

  • Agency: NCI NIH HHS, Id: K01 CA087580
  • Agency: NCI NIH HHS, Id: R01 CA100302

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