A leucine-rich nuclear export signal in the p53 tetramerization domain: regulation of subcellular localization and p53 activity by NES masking

Appropriate subcellular localization is crucial for regulating p53 function . We show that p53 export is mediated by a highly conserved leucine-rich nu clear export signal (NES) located in its tetramerization domain, Mutation o f NES residues prevented p53 export and hampered tetramer formation. Althou gh the p53-binding protein MDM2 has an NES and has been proposed to mediate p53 export, we show that the intrinsic p53 NES is both necessary and suffi cient for export. This report also demonstrates that the cytoplasmic locali zation of p53 in neuroblastoma cells is due to its hyperactive nuclear expo rt: p53 in these cells can be trapped in the nucleus by the export-inhibiti ng drug leptomycin B or by binding a p53-tetramerization domain peptide tha t masks the NES. We propose a model in which regulated p53 tetramerization occludes its NES, thereby ensuring nuclear retention of the DNA-binding for m. We suggest that attenuation of p53 function involves the conversion of t etramers into monomers or dimers, in which the NES is exposed to the protei ns which mediate their export to the cytoplasm.