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Cell Cycle. 2008 Mar 1;7(5):670-82. Epub 2008 Jan 31.

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

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  • 1Laboratory of Molecular Oncology and Cell Cycle Regulation, Department of Medicine (Hematology/Oncology), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.

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.

PMID:
18382127
[PubMed - indexed for MEDLINE]
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