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

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.

Pubmed ID: 18382127

Authors

  • Yang W
  • Dicker DT
  • Chen J
  • El-Deiry WS

Journal

Cell cycle (Georgetown, Tex.)

Publication Data

March 1, 2008

Associated Grants

  • Agency: NCI NIH HHS, Id: CA-105008
  • Agency: NCI NIH HHS, Id: CA-75138
  • Agency: NCI NIH HHS, Id: CA-97100
  • Agency: NCI NIH HHS, Id: CA-98101

Mesh Terms

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