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 RIS Download
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