p53 stabilization and transactivation by a von Hippel-Lindau protein

Mol Cell. 2006 May 5;22(3):395-405. doi: 10.1016/j.molcel.2006.04.006.

Abstract

von Hippel-Lindau (VHL) disease is a rare autosomal dominant cancer syndrome. Although hypoxia-inducible factor-alpha (HIFalpha) is a well-documented substrate of von Hippel-Lindau tumor suppressor protein (pVHL), it remains unclear whether the dysregulation of HIF is sufficient to account for de novo tumorigenesis in VHL-deleted cells. Here we found that pVHL directly associates with and stabilizes p53 by suppressing Mdm2-mediated ubiquitination and nuclear export of p53. Moreover, upon genotoxic stress, pVHL invoked an interaction between p53 and p300 and the acetylation of p53, which ultimately led to an increase in p53 transcriptional activity and p53-mediated cell cycle arrest and apoptosis. These results suggest that the tumor suppressor pVHL has an unexpected function to upregulate the tumor suppressor p53.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Active Transport, Cell Nucleus
  • Apoptosis
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle
  • Cell Cycle Proteins / metabolism
  • Cell Nucleus / metabolism
  • DNA Damage / genetics
  • DNA-Binding Proteins / metabolism
  • Elongin
  • Humans
  • Lysine / metabolism
  • Protein Binding
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Thermodynamics
  • Transcription Factors / metabolism
  • Transcriptional Activation*
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / chemistry
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism*
  • Tumor Suppressor Proteins / metabolism
  • Ubiquitin / metabolism
  • Von Hippel-Lindau Tumor Suppressor Protein / metabolism*

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Elongin
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • Ubiquitin
  • Proto-Oncogene Proteins c-mdm2
  • Von Hippel-Lindau Tumor Suppressor Protein
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein-Serine-Threonine Kinases
  • VHL protein, human
  • Lysine