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...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2003-12, Vol.302 (5652), p.1972-1975
Main Authors: Li, Muyang, Brooks, Christopher L., Wu-Baer, Foon, Chen, Delin, Baer, Richard, Gu, Wei
Format: Article
Language:English
Subjects:
Active Transport, Cell Nucleus
Analysis
Animals
Biochemistry
Biological and medical sciences
Cell Line, Tumor
Cell lines
Cell nucleus
Cell Nucleus - metabolism
Cells
Cells, Cultured
Cellular biology
Cytoplasm
Cytoplasm - metabolism
Fractions
General aspects
HEK293 cells
Humans
Hypoxia
Kidney cells
Mdm2 protein
Medical research
Medical sciences
Mice
Mice, Knockout
Mutation
nuclear export
Nuclear Proteins
Pathology
Physiological regulation
Protein Transport
Proteins
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins c-mdm2
Recombinant Fusion Proteins - metabolism
Transcription factors
Transfection
Tumor suppressor genes
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - metabolism
Tumors
Tumour suppressor genes
Ubiquitin - genetics
Ubiquitin - metabolism
Ubiquitin-proteasome system
ubiquitination
Ubiquitins
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Summary: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.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.1091362