https://pubmed.ncbi.nlm.nih.gov/27347849/

 Nat Cell Biol

. 2016 Aug;18(8):897-909.

 doi: 10.1038/ncb3380. Epub 2016 Jun 27.

Proteasome machinery is instrumental in a common gain-of-function program of the p53 missense mutants in cancer

Dawid Walerych 1, Kamil Lisek 1 2, Roberta Sommaggio 3, Silvano Piazza 1, Yari Ciani 1, Emiliano Dalla 1, Katarzyna Rajkowska 1, Katarzyna Gaweda-Walerych 1 4, Eleonora Ingallina 1 2, Claudia Tonelli 5, Marco J Morelli 6, Angela Amato 7, Vincenzo Eterno 7, Alberto Zambelli 7 8, Antonio Rosato 3 9, Bruno Amati 5 6, Jacek R Wiśniewski 10, Giannino Del Sal 1 2

Affiliations 

• PMID: 27347849
 
• DOI: 10.1038/ncb3380

Abstract

In cancer, the tumour suppressor gene TP53 undergoes frequent missense mutations that endow mutant p53 proteins with oncogenic properties. Until now, a universal mutant p53 gain-of-function program has not been defined. By means of multi-omics: proteome, DNA interactome (chromatin immunoprecipitation followed by sequencing) and transcriptome (RNA sequencing/microarray) analyses, we identified the proteasome machinery as a common target of p53 missense mutants. The mutant p53-proteasome axis globally affects protein homeostasis, inhibiting multiple tumour-suppressive pathways, including the anti-oncogenic KSRP-microRNA pathway. In cancer cells, p53 missense mutants cooperate with Nrf2 (NFE2L2) to activate proteasome gene transcription, resulting in resistance to the proteasome inhibitor carfilzomib. Combining the mutant p53-inactivating agent APR-246 (PRIMA-1MET) with the proteasome inhibitor carfilzomib is effective in overcoming chemoresistance in triple-negative breast cancer cells, creating a therapeutic opportunity for treatment of solid tumours and metastasis with mutant p53.

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