Abstract
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.
Highlights
The p53 protein is a key regulator of cell cycle arrest, DNA repair, and apoptosis and has been characterized as “the guardian of the genome” [1, 2]
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 demonstrated that the HECT-type E3 ubiquitin ligases Smurf1 and -2 enhance the heterodimerization of MDM2 and MDMX and block the homodimerization of MDM2
Summary
E3, ubiquitin ligase; HA, hemagglutinin; GST, glutathione S-transferase; co-IP, co-immunoprecipitation; siRNA, small interfering RNA; MEF, mouse embryonic fibroblast. Smurf1/2 Promotes p53 Degradation blocks the homodimerization of MDM2 and inhibits MDM2 self-ubiquitylation [27,28,29]. In such a way, MDMX regulates the activity of MDM2 and furthers the level of p53. MDMX regulates the activity of MDM2 and furthers the level of p53 It remains unclear how the heterodimerization of MDM2 and MDMX occurs. We demonstrated that the HECT-type E3 ubiquitin ligases Smurf and -2 enhance the heterodimerization of MDM2 and MDMX and block the homodimerization of MDM2. We provide evidence that Smurf and -2 play an important role in maintenance of MDM2 stability, by such a way Smurf and -2 inhibit p53 activity and block apoptosis
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