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Identification of p53 sequence elements that are required for MDM2-mediated nuclear export.
1Department of Cancer Cell Biology, Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115, USA.
Molecular and Cellular Biology
|November 20, 2001
Summary
MDM2 protein controls the movement of p53 between the nucleus and cytoplasm. Ubiquitination of p53 by MDM2 triggers conformational changes, activating p53 nuclear export.
Area of Science:
- Molecular Biology
- Cell Biology
- Protein Interactions
Background:
- MDM2 differentially regulates p53 and p73 subcellular localization.
- p53 undergoes nuclear export mediated by MDM2, while p73 forms nuclear aggregates with MDM2.
Purpose of the Study:
- To identify structural elements in p53 responsible for MDM2-mediated nuclear export.
- To elucidate the mechanism of p53 nuclear export regulation by MDM2.
Main Methods:
- Utilized p53/p73 chimeric proteins to map functional regions.
- Investigated the role of specific lysine residues and protein domains in p53 nuclear export.
- Analyzed p53 mutants with substitutions in key lysine residues (6KR, 6KA).
Main Results:
- Three regions of p53 are critical for MDM2-mediated nuclear export.
- The DNA binding domain (DBD) maintains p53 conformation for nuclear export sequence (NES) function.
- Ubiquitination of C-terminal lysines (e.g., 6KR, 6KA mutants) is an initial step for p53 nuclear export.
- Lysine 305 and the region between DBD and oligomerization domain are crucial for p53NES activation.
- p53NES activation can occur without disrupting the p53 tetramer.
Conclusions:
- MDM2-mediated p53 nuclear export is dependent on ubiquitination-induced conformational changes.
- Specific structural regions and post-translational modifications dictate p53 nucleocytoplasmic shuttling.
- The mechanism of p53 nuclear export is distinct from p73 localization patterns.