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

Wensheng Yang, David T. Dicker, Jiandong Chen and Wafik S. El-Deiry

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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 14-3-3σ 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.

Authors

Wensheng Yang

University of Pennsylvania School of Medicine; Philadelphia, PA

David T. Dicker

University of Pennsylvania School of Medicine; Philadelphia, PA

Jiandong Chen

H. Lee Moffitt Cancer Center and Research Institute; Tampa, FL

Wafik S. El-Deiry

University of Pennsylvania School of Medicine; Philadelphia, PA

Purchase article for $19

Subscribe to this journal for $129/year