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

EMBO J. 1999 Mar 15;18(6):1660-72. doi: 10.1093/emboj/18.6.1660.


Appropriate subcellular localization is crucial for regulating p53 function. We show that p53 export is mediated by a highly conserved leucine-rich nuclear export signal (NES) located in its tetramerization domain. Mutation of NES residues prevented p53 export and hampered tetramer formation. Although 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 sufficient for export. This report also demonstrates that the cytoplasmic localization of p53 in neuroblastoma cells is due to its hyperactive nuclear export: p53 in these cells can be trapped in the nucleus by the export-inhibiting drug leptomycin B or by binding a p53-tetramerization domain peptide that masks the NES. We propose a model in which regulated p53 tetramerization occludes its NES, thereby ensuring nuclear retention of the DNA-binding form. We suggest that attenuation of p53 function involves the conversion of tetramers into monomers or dimers, in which the NES is exposed to the proteins which mediate their export to the cytoplasm.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3T3 Cells
  • Amino Acid Sequence
  • Animals
  • Cattle
  • Conserved Sequence
  • HeLa Cells
  • Humans
  • Leucine
  • Macromolecular Substances
  • Mice
  • Models, Molecular
  • Mutagenesis, Site-Directed
  • Neuroblastoma
  • Osteosarcoma
  • Protein Structure, Secondary
  • Rabbits
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / chemistry
  • Sequence Alignment
  • Signal Transduction
  • Subcellular Fractions / metabolism
  • Transfection
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / chemistry*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Xenopus
  • Zebrafish


  • Macromolecular Substances
  • Recombinant Proteins
  • Tumor Suppressor Protein p53
  • Leucine