title: MDM2 can promote the ubiquitination, nuclear export, and degradation of p53 in the absence of direct binding.
abstract: MDM2 can bind the N terminus of p53 and promote its ubiquitination and export from the nucleus to the cytoplasm, where p53 can then be degraded by cytoplasmic proteasomes. Several studies have reported that an intact MDM2 binding domain is necessary for p53 to be targeted for ubiquitination, nuclear export, and degradation by MDM2. In the current study, we examined whether the MDM2 binding domain of p53 could be provided in trans through oligomerization between two p53 molecules. p53 proteins mutated in their MDM2 binding domains were unable to bind MDM2 directly and were resistant to MDM2-mediated ubiquitination, nuclear export, and degradation when expressed with MDM2 alone. However, these same p53 mutants formed a complex with MDM2 and were efficiently ubiquitinated, exported from the nucleus, and degraded when co-expressed with MDM2 and wild-type p53. Moreover, this effect required MDM2 binding by wild-type p53 as well as oligomerization between wild-type p53 and the MDM2 binding-deficient p53 mutants. Taken together, these results support a model whereby MDM2 binding-deficient forms of p53 can bind MDM2 indirectly through oligomerization with wild-type p53 and are subsequently targeted for ubiquitination, nuclear export, and degradation. These findings may have important implications regarding the DNA damage response of p53.
authors.affiliation: Department of Cancer Cell Biology, Harvard University School of Public Health, Boston, Massachusetts 02115, USA.
authors.forename: T
authors.initials: T
authors.lastname: Inoue
authors.forename: R K
authors.initials: RK
authors.lastname: Geyer
authors.forename: D
authors.initials: D
authors.lastname: Howard
authors.forename: Z K
authors.initials: ZK
authors.lastname: Yu
authors.forename: C G
authors.initials: CG
authors.lastname: Maki
mesh_terms: D021581:Active Transport, Cell Nucleus; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004249:DNA Damage; D000939:Epitopes; D016158:Genes, p53 / Q000235:genetics; D006801:Humans; D015151:Immunoblotting; D008856:Microscopy, Fluorescence; D009154:Mutation; D009687:Nuclear Proteins; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism* / Q000502:physiology*; D051736:Proto-Oncogene Proteins c-mdm2; D013312:Stress, Physiological; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D000939:Epitopes; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2