Protein Synthesis and Degradation
Smad Ubiquitylation Regulatory Factor 1/2 (Smurf1/2) Promotes p53 Degradation by Stabilizing the E3 Ligase MDM2*

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The tumor suppressor p53 protein is tightly regulated by a ubiquitin-proteasomal degradation mechanism. Several E3 ubiquitin ligases, including MDM2 (mouse double minute 2), have been reported to play an essential role in the regulation of p53 stability. However, it remains unclear how the activity of these E3 ligases is regulated. Here, we show that the HECT-type E3 ligase Smurf1/2 (Smad ubiquitylation regulatory factor 1/2) promotes p53 degradation by enhancing the activity of the E3 ligase MDM2. We provide evidence that the role of Smurf1/2 on the p53 stability is not dependent on the E3 activity of Smurf1/2 but rather is dependent on the activity of MDM2. We find that Smurf1/2 stabilizes MDM2 by enhancing the heterodimerization of MDM2 with MDMX, during which Smurf1/2 interacts with MDM2 and MDMX. We finally provide evidence that Smurf1/2 regulates apoptosis through p53. To our knowledge, this is the first report to demonstrate that Smurf1/2 functions as a factor to stabilize MDM2 protein rather than as a direct E3 ligase in regulation of p53 degradation.

E3 Ubiquitin Ligase
p53
Protein Degradation
Ubiquitin
Ubiquitination
MDM2
MDMX
Smurf

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*

The work was supported by National Basic Research Program Grants 2007CB914601, 2006CB910802, 2009CB918402, and 2010CB912202, National Natural Science Foundation Project Grants 30830029 and 30800177, National Key Technologies R & D Program for New Drugs Grants 2009ZX09503-002 and 2009ZX09301-002, and State Key Laboratory of Proteomics Grant K200802.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1 and Table S1.