HIPK2 neutralizes MDM2 inhibition rescuing p53 transcriptional activity and apoptotic function

Oncogene. 2004 Jul 1;23(30):5185-92. doi: 10.1038/sj.onc.1207656.

Abstract

The p53 oncosuppressor protein is subject to negative regulation by MDM2, which efficiently inhibits its activity through an autoregulatory loop. In response to stress, however, p53 undergoes post-translational modifications that allow the protein to escape MDM2 control, accumulate, and become active. Recent studies have shown that, following DNA damage, the HIPK2 serine/threonine kinase binds and phosphorylates p53, inducing p53 transcriptional activity and apoptotic function. Here, we investigated the role of HIPK2 in the activation of p53 in the presence of MDM2. We found that HIPK2 rescues p53 transcriptional activity overcoming MDM2 inhibition, and that restoration of this p53 function induces apoptosis. Recovery of p53-dependent apoptosis is achieved by preventing p53 nuclear export and ubiquitination mediated by MDM2 in vitro and in vivo following genotoxic stress. These results shed new light on the mechanisms by which the HIPK2/p53 pathway promotes apoptosis and suppression of tumorigenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Antineoplastic Agents / pharmacology
  • Apoptosis* / genetics
  • Blotting, Western
  • Carrier Proteins / drug effects
  • Carrier Proteins / metabolism*
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Cisplatin / pharmacology
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology
  • Cysteine Proteinase Inhibitors / pharmacology
  • DNA Damage
  • Humans
  • Leupeptins / pharmacology
  • Luciferases / metabolism
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Nuclear Proteins / antagonists & inhibitors*
  • Nuclear Proteins / drug effects
  • Osteosarcoma / metabolism
  • Osteosarcoma / pathology
  • Precipitin Tests
  • Protein-Serine-Threonine Kinases / drug effects
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins / drug effects
  • Proto-Oncogene Proteins c-mdm2
  • Transcriptional Activation*
  • Tumor Suppressor Protein p53 / drug effects
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Ubiquitin / metabolism

Substances

  • Antineoplastic Agents
  • Carrier Proteins
  • Cysteine Proteinase Inhibitors
  • Leupeptins
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Tumor Suppressor Protein p53
  • Ubiquitin
  • Luciferases
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • HIPK2 protein, human
  • Protein-Serine-Threonine Kinases
  • Cisplatin
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde