A stapled p53 helix overcomes HDMX-mediated suppression of p53.

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.
Mesh Terms:
Amino Acid Sequence, Animals, Binding Sites, Binding, Competitive, Cell Line, Tumor, Humans, Mice, Mice, Inbred NOD, Nuclear Proteins, Protein Engineering, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-mdm2, Tumor Suppressor Protein p53
Cancer Cell
Date: Nov. 16, 2010
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