title: Targeted inactivation of Mdm2 RING finger E3 ubiquitin ligase activity in the mouse reveals mechanistic insights into p53 regulation.
abstract: 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.
authors.affiliation: Department of Radiation Oncology, School of Medicine, the University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7512, USA.
authors.forename: Koji
authors.initials: K
authors.lastname: Itahana
authors.forename: Hua
authors.initials: H
authors.lastname: Mao
authors.forename: Aiwen
authors.initials: A
authors.lastname: Jin
authors.forename: Yoko
authors.initials: Y
authors.lastname: Itahana
authors.forename: Hilary V
authors.initials: HV
authors.lastname: Clegg
authors.forename: Mikael S
authors.initials: MS
authors.lastname: Lindström
authors.forename: Krishna P
authors.initials: KP
authors.lastname: Bhat
authors.forename: Virginia L
authors.initials: VL
authors.lastname: Godfrey
authors.forename: Gerard I
authors.initials: GI
authors.lastname: Evan
authors.forename: Yanping
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002478:Cells, Cultured; D004249:DNA Damage; D015536:Down-Regulation; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism / Q000528:radiation effects; D005720:Gamma Rays; D018507:Gene Expression Regulation, Developmental / Q000528:radiation effects; D005838:Genotype; D005865:Gestational Age; D006720:Homozygote; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D046988:Proteasome Endopeptidase Complex