Mutational analysis reveals a dual role of Mdm2 acidic domain in the regulation of p53 stability.
The exact role of the central acidic domain of Mdm2 in p53 degradation remains unclear. We therefore performed a systematic and comprehensive analysis of the acidic domain using a series of short deletions and found that only a minor part of the domain was indispensable for Mdm2-mediated p53 ubiquitylation. Moreover, we identified a short stretch of acidic amino acids required for p53 degradation but not ubiquitylation, indicating that, in addition to p53 ubiquitylation, the acidic domain might be involved in a critical post-ubiquitylation step in p53 degradation. Rather than representing a single functional domain, different parts of the acidic region perform separate functions in p53 degradation, suggesting that it might be possible to therapeutically target them independently.
Department of Biology, Faculty of Medicine, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic.
Pavlina
P
Dolezelova
Katerina
K
Cetkovska
Karen H
KH
Vousden
Stjepan
S
Uldrijan
D000595:Amino Acid Sequence; D018797:Cell Cycle Proteins; D004252:DNA Mutational Analysis; D017353:Gene Deletion; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D008954:Models, Biological; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry / Q000502:physiology; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000502:physiology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D017386:Sequence Homology, Amino Acid; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000378:metabolism; D025801:Ubiquitin / Q000737:chemistry
D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2