title: Inhibition of p53 DNA binding function by the MDM2 protein acidic domain.
abstract: MDM2 regulates p53 predominantly by promoting p53 ubiquitination. However, ubiquitination-independent mechanisms of MDM2 have also been implicated. Here we show that MDM2 inhibits p53 DNA binding activity in vitro and in vivo. MDM2 binding promotes p53 to adopt a mutant-like conformation, losing reactivity to antibody Pab1620, while exposing the Pab240 epitope. The acidic domain of MDM2 is required to induce p53 conformational change and inhibit p53 DNA binding. Alternate reading frame binding to the MDM2 acidic domain restores p53 wild type conformation and rescues DNA binding activity. Furthermore, histone methyl transferase SUV39H1 binding to the MDM2 acidic domain also restores p53 wild type conformation and allows p53-MDM2-SUV39H1 complex to bind DNA. These results provide further evidence for an ubiquitination-independent mechanism of p53 regulation by MDM2 and reveal how MDM2-interacting repressors gain access to p53 target promoters and repress transcription. Furthermore, we show that the MDM2 inhibitor Nutlin cooperates with the proteasome inhibitor Bortezomib by stimulating p53 DNA binding and transcriptional activity, providing a rationale for combination therapy using proteasome and MDM2 inhibitors.
authors: Molecular Oncology Department, Moffitt Cancer Center, Tampa, Florida 33612, USA.
authors: Brittany
authors: B
authors: Cross
authors: Lihong
authors: L
authors: Chen
authors: Qian
authors: Q
authors: Cheng
authors: Baozong
authors: B
authors: Li
authors: Zhi-Min
authors: ZM
authors: Yuan
authors: Jiandong
authors: J
authors: Chen
mesh_terms: D000906:Antibodies / Q000737:chemistry; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002460:Cell Line; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D000939:Epitopes / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000502:physiology; D011480:Protease Inhibitors / Q000494:pharmacology; D061988:Proteasome Inhibitors; D017434:Protein Structure, Tertiary; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects / Q000502:physiology
chemical_list: D000906:Antibodies; D001897:Boronic Acids; D000939:Epitopes; D046912:Multiprotein Complexes; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D012097:Repressor Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000069286:Bortezomib; D004247:DNA; C407843:SUV39H1 protein, human; D008780:Methyltransferases; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2