Regulation of P53 Nuclear Export Through Sequential Changes in Conformation and Ubiquitination.
From: Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA.
The Journal of biological chemistry
- Publish Date: May 2007
- ISSN: 0021-9258
- Volume: 282
- Issue: 19
- Pages: 14616-25
- Medium: Print
- Language: English
- Citation (JAMA): Nie Linghu, Sasaki Mark, Maki Carl G, et al. Regulation of P53 Nuclear Export Through Sequential Changes in Conformation and Ubiquitination.. J. Biol. Chem. May 2007;282:14616-25
Abstract
Wild-type p53 is a conformationally labile protein that undergoes nuclear-cytoplasmic shuttling. MDM2-mediated ubiquitination promotes p53 nuclear export by exposing or activating a nuclear export signal (NES) in the C terminus of p53. We observed that cancer-derived p53s with a mutant (primary antibody 1620-/pAb240+) conformation localized in the cytoplasm to a greater extent and displayed increased susceptibility to ubiquitination than p53s with a more wild-type (primary antibody 1620+/pAb240-) conformation. The cytoplasmic localization of mutant p53s required the C-terminal NES and an intact ubiquitination pathway. Mutant p53 ubiquitination occurred at lysines in both the DNA-binding domain (DBD) and C terminus. Interestingly, Lys to Arg mutations that inhibited ubiquitination restored nuclear localization to mutant p53 but had no apparent effect on p53 conformation. Further studies revealed that wild-type p53, like mutant p53, is ubiquitinated by MDM2 in both the DBD and C terminus and that ubiquitination in both regions contributes to its nuclear export. MDM2 binding can induce a conformational change in wild-type p53, but this conformational change is insufficient to promote p53 nuclear export in the absence of MDM2 ubiquitination activity. Taken together, these results support a stepwise model for mutant and wild-type p53 nuclear export. In this model, the conformational change induced by either the cancer-derived mutation or MDM2 binding precedes p53 ubiquitination. The addition of ubiquitin to DBD and C-terminal lysines then promotes nuclear export via the C-terminal NES.
Mesh Headings (Keywords): Active Transport, Cell Nucleus, Animals, Bone Neoplasms, Cell Nucleus, Cells, Cultured, Cytoplasm, Embryo, Mammalian, Fibroblasts, Humans, Immunoblotting, Mice, Mice, Knockout, Molecular Conformation, Mutation, Nuclear Export Signals, Osteosarcoma, Protein Binding, Protein Conformation, Protein Processing, Post-Translational, Proto-Oncogene Proteins c-mdm2, Transfection, Tumor Suppressor Protein p53, Ubiquitin
Check for Full Text / PubMed Unique Identifier (PMID): 17371868
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