Targeted inactivation of Mdm2 RING finger E3 ubiquitin ligase activity in the mouse reveals mechanistic insights into p53 regulation.
Journal:
Cancer Cell 2007 OctAuthors:
Itahana K, Mao H, Jin A, Itahana Y, Clegg HV, Lindström MS, Bhat KP, Godfrey VL, Evan GI, Zhang Y
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 demon
...[more]strated 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.[less]
Mesh Headings:
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