The contribution of the acidic domain of MDM2 to p53 and MDM2 stability.
p53 and MDM2 are both degraded by the ubiquitin-proteasome pathway. MDM2 binds p53 and promotes its rapid degradation. MDM2 is an E3 ligase that activates self and p53 ubiquitylation. Moreover, MDM2 nuclear-cytoplasmic shuttling contributes to p53 degradation in the cytoplasm. We have identified a new region of MDM2 which regulates the stability of both p53 and MDM2. The first 50 amino-acids of the MDM2 acidic domain (222-272) contribute to MDM2 and MDM2-mediated p53 degradation by a mechanism which is independent of either MDM2 E3-ligase activity or MDM2 nucleo-cytoplasmic shuttling. The transcriptional coactivator p300 could have been involved, since it binds to the MDM2 acidic domain. However, we found that p300 stabilises MDM2, even in absence of an intact acidic domain, indicating that the MDM2 acidic region contributes to proteolysis independently of p300. We propose that the MDM2 acidic domain is required for unbiquitylated MDM2 and p53 to be degraded by cytoplasmic proteasomes.
Argentini
M
M
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, 1 rue Laurent Fries, BP 163, 67404 Illkirch cédex, France.
Barboule
N
N
Wasylyk
B
B
D000143:Acids; D021581:Active Transport, Cell Nucleus; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D008025:Ligases / Q000378:metabolism*; D051379:Mice; D009687:Nuclear Proteins; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D021382:Protein Sorting Signals; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D014452:Ubiquitins / Q000378:metabolism*
D000143:Acids; D009687:Nuclear Proteins; D021382:Protein Sorting Signals; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D014452:Ubiquitins; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases; D008025:Ligases