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

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


  • Itahana K
  • Mao H
  • Jin A
  • Itahana Y
  • Clegg HV
  • Lindström MS
  • Bhat KP
  • Godfrey VL
  • Evan GI
  • Zhang Y


Cancer cell

Publication Data

October 15, 2007

Associated Grants

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

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