A Stapled p53 Helix Overcomes HDMX-Mediated Suppression of p53

作者：Bernal Federico; Wade Mark; Godes Marina; Davis Tina N; Whitehead David G; Kung Andrew L; Wahl Geoffrey M; Walensky Loren D^*

来源：Cancer Cell, 2010, 18(5): 411-422.

DOI：10.1016/j.ccr.2010.10.024

Cancer cells neutralize p53 by deletion, mutation, proteasomal degradation, or sequestration to achieve a pathologic survival advantage. Targeting the E3 ubiquitin ligase HDM2 can lead to a therapeutic surge in p53 levels. However, the efficacy of HDM2 inhibition can be compromised by overexpression of HDMX, an HDM2 homolog that binds and sequesters p53. Here, we report that a stapled p53 helix preferentially targets HDMX, blocks the formation of inhibitory p53-HDMX complexes, induces p53-dependent transcriptional upregulation, and thereby overcomes HDMX-mediated cancer resistance in vitro and in vivo. Importantly, our analysis of p53 interaction dynamics provides a blueprint for reactivating the p53 pathway in cancer by matching HDM2, HDMX, or dual inhibitors to the appropriate cellular context.

• 出版日期2010-11-16