Mono- versus polyubiquitination: differential control of p53 fate by Mdm2.
Although Mdm2-mediated ubiquitination is essential for both degradation and nuclear export of p53, the molecular basis for the differential effects of Mdm2 remains unknown. Here we show that low levels of Mdm2 activity induce monoubiquitination and nuclear export of p53, whereas high levels promote p53's polyubiquitination and nuclear degradation. A p53-ubiquitin fusion protein that mimics monoubiquitinated p53 was found to accumulate in the cytoplasm in an Mdm2-independent manner, indicating that monoubiquitination is critical for p53 trafficking. These results clarify the nature of ubiquitination-mediated p53 regulation and suggest that distinct mechanisms regulate p53 function in accordance with the levels of Mdm2 activity.
Li
Muyang
M
Institute for Cancer Genetics and Department of Pathology, College of Physicians & Surgeons, Columbia University, 1150 St. Nicholas Avenue, New York, NY 10032, USA.
Brooks
Christopher L
CL
Wu-Baer
Foon
F
Chen
Delin
D
Baer
Richard
R
Gu
Wei
W
D021581:Active Transport, Cell Nucleus; D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009687:Nuclear Proteins; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*
D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2