FKBP25, a novel regulator of the p53 pathway, induces the degradation of MDM2 and activation of p53

FEBS Lett. 2009 Feb 18;583(4):621-6. doi: 10.1016/j.febslet.2009.01.009. Epub 2009 Jan 21.

Abstract

The p53 tumour suppressor protein is tightly controlled by the E3 ubiquitin ligase, mouse double minute 2 (MDM2), but maintains MDM2 expression as part of a negative feedback loop. We have identified the immunophilin, 25kDa FK506-binding protein (FKBP25), previously shown to be regulated by p53-mediated repression, as an MDM2-interacting partner. We show that FKBP25 stimulates auto-ubiquitylation and proteasomal degradation of MDM2, leading to the induction of p53. Depletion of FKBP25 by siRNA leads to increased levels of MDM2 and a corresponding reduction in p53 and p21 levels. These data are consistent with the idea that FKBP25 contributes to regulation of the p53-MDM2 negative feedback loop.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Escherichia coli / genetics
  • Gene Expression Regulation, Neoplastic*
  • Genes, Reporter
  • Glutathione Transferase / metabolism
  • HCT116 Cells
  • Humans
  • Luciferases / metabolism
  • Mice
  • Proteasome Endopeptidase Complex / genetics
  • Proteasome Endopeptidase Complex / metabolism
  • Proto-Oncogene Proteins c-mdm2 / genetics
  • Proto-Oncogene Proteins c-mdm2 / metabolism*
  • RNA, Small Interfering / metabolism
  • Recombinant Fusion Proteins / metabolism
  • Tacrolimus Binding Proteins / genetics
  • Tacrolimus Binding Proteins / metabolism*
  • Transfection
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination

Substances

  • Cyclin-Dependent Kinase Inhibitor p21
  • RNA, Small Interfering
  • Recombinant Fusion Proteins
  • Tumor Suppressor Protein p53
  • FKBP3 protein, human
  • Luciferases
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • Ubiquitin-Protein Ligases
  • Glutathione Transferase
  • Proteasome Endopeptidase Complex
  • Tacrolimus Binding Proteins