CARPs enhance p53 turnover by degrading 14-3-3sigma and stabilizing MDM2

Cell Cycle. 2008 Mar 1;7(5):670-82. doi: 10.4161/cc.7.5.5701. Epub 2008 Jan 31.

Abstract

CARP1 and CARP2 proteins (CARPs) are E3 ligases that target p53 as well as phospho-p53 for degradation. Because MDM2 is a critical regulator of p53 turnover, we investigated and found that CARPs associate with MDM2. We provide evidence that CARPs stabilize MDM2 by inhibiting MDM2 self-ubiquitination. CARPs together with MDM2 enhance p53 degradation, thereby inhibiting p53-mediated cell death. CARP protein levels correlate with MDM2 levels including under hypoxia where both are reduced. CARP2 was found to target 14-3-3sigma for degradation, leading to MDM2 stabilization. MDMX, a homolog of MDM2, is not absolutely required for MDM2 stabilization by CARPs, although overexpression of CARP2 enhances MDM2/MDMX interaction. Taken together, our study identifies novel mechanisms by which CARP proteins regulate the p53 signaling pathway.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 14-3-3 Proteins
  • Animals
  • Apoptosis Regulatory Proteins
  • Biomarkers, Tumor / metabolism*
  • Carrier Proteins / metabolism*
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Exonucleases / metabolism*
  • Exoribonucleases
  • Humans
  • Mice
  • Neoplasm Proteins / metabolism*
  • Nerve Tissue Proteins / metabolism*
  • Protein Binding
  • Protein Processing, Post-Translational
  • Proto-Oncogene Proteins c-mdm2 / metabolism*
  • Thermodynamics
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • 14-3-3 Proteins
  • Apoptosis Regulatory Proteins
  • Biomarkers, Tumor
  • CA11 protein, human
  • CCAR1 protein, human
  • Carrier Proteins
  • Cell Cycle Proteins
  • Neoplasm Proteins
  • Nerve Tissue Proteins
  • Tumor Suppressor Protein p53
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • Exonucleases
  • Exoribonucleases
  • SFN protein, human