title: Mdm2 is critically and continuously required to suppress lethal p53 activity in vivo.
abstract: There is currently much interest in the idea of restoring p53 activity in tumor cells by inhibiting Hdm2/Mdm2. However, it has remained unclear whether this would also activate p53 in normal cells. Using a switchable endogenous p53 mouse model, which allows rapid and reversible toggling of p53 status between wild-type and null states, we show that p53 is spontaneously active in all tested tissues of mdm2-deficient mice, triggering fatal pathologies that include ablation of classically radiosensitive tissues. In apoptosis-resistant tissues, spontaneous unbuffered p53 activity triggers profound inhibition of cell proliferation. Such acute spontaneous p53 activity occurs in the absence of any detectable p53 posttranslational modification, DNA damage, or p19ARF signaling and triggers rapid p53 degradation.
authors.affiliation: Cancer Research Institute and Department of Cellular and Molecular Pharmacology, Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California 94143, USA.
authors.forename: Ingo
authors.initials: I
authors.lastname: Ringshausen
authors.forename: Clodagh C
authors.initials: CC
authors.lastname: O'Shea
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Finch
authors.forename: Lamorna Brown
authors.initials: LB
authors.lastname: Swigart
authors.forename: Gerard I
authors.initials: GI
authors.lastname: Evan
mesh_terms: D020823:ADP-Ribosylation Factor 1 / Q000502:physiology; D000818:Animals; D004249:DNA Damage; D007093:Imidazoles; D051379:Mice; D010766:Phosphorylation; D010879:Piperazines; D051736:Proto-Oncogene Proteins c-mdm2 / Q000172:deficiency / Q000502:physiology*; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D007093:Imidazoles; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; D013629:Tamoxifen; C016601:afimoxifene; C482205:nutlin 3; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D020823:ADP-Ribosylation Factor 1