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Autoinhibition of MDMX by intramolecular p53 mimicry

2015; National Academy of Sciences; Volume: 112; Issue: 15 Linguagem: Inglês

10.1073/pnas.1420833112

1091-6490

Lihong Chen, Wade M. Borcherds, Shaofang Wu, Andreas Becker, E. Schönbrunn, Gary W. Daughdrill, Jiandong Chen,

Ubiquitin and proteasome pathways

Significance MDMX protein is a critical regulator of p53 and a novel drug target. The current generation of MDM2 inhibitors does not inhibit MDMX. Therefore, their therapeutic efficacy will be influenced by poorly characterized MDMX functional status in tumors. Efforts to develop MDMX inhibitors have been largely unsuccessful, indicating gaps in our understanding of the structure and regulation of MDMX. This study provides evidence that MDMX-p53 binding is regulated by an autoinhibitory mechanism that involves intramolecular interaction in MDMX through p53 mimicry. The results suggest a mechanism by which DNA damage signaling inhibits MDMX and activates p53.