Nucleolar Arf Sequesters Mdm2 and Activates p53

Nat Cell Biol. 1999 May;1(1):20-6. doi: 10.1038/8991.

Abstract

The Ink4/Arf locus encodes two tumour-suppressor proteins, p16Ink4a and p19Arf, that govern the antiproliferative functions of the retinoblastoma and p53 proteins, respectively. Here we show that Arf binds to the product of the Mdm2 gene and sequesters it into the nucleolus, thereby preventing negative-feedback regulation of p53 by Mdm2 and leading to the activation of p53 in the nucleoplasm. Arf and Mdm2 co-localize in the nucleolus in response to activation of the oncoprotein Myc and as mouse fibroblasts undergo replicative senescence. These topological interactions of Arf and Mdm2 point towards a new mechanism for p53 activation.

Publication types

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

MeSH terms

  • 3T3 Cells
  • ADP-Ribosylation Factors / genetics
  • ADP-Ribosylation Factors / metabolism*
  • Animals
  • Cell Nucleolus / metabolism*
  • Cell Nucleolus / ultrastructure
  • Cellular Senescence
  • Feedback
  • Fibroblasts / cytology
  • Fibroblasts / physiology
  • Gene Expression Regulation
  • Genes, myc
  • Genes, p53
  • Mice
  • Nuclear Proteins*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-mdm2
  • Recombinant Proteins / metabolism
  • Transfection
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Recombinant Proteins
  • Tumor Suppressor Protein p53
  • Mdm2 protein, mouse
  • Proto-Oncogene Proteins c-mdm2
  • ADP-Ribosylation Factors