Mutant p53 Prolongs NF-κB Activation and Promotes Chronic Inflammation and Inflammation-Associated Colorectal Cancer

Tomer Cooks, Ioannis S. Pateras, Ohad Tarcic, Hilla Solomon, Aaron J. Schetter, Sylvia Wilder, Guillermina Lozano, Eli Pikarsky, Tim Forshew, Nitzan Rozenfeld, Noam Harpaz, Steven Itzkowitz, Curtis C. Harris, Varda Rotter, Vassilis G. Gorgoulis, Moshe Oren

Research output: Contribution to journalArticlepeer-review

298 Scopus citations

Abstract

The tumor suppressor p53 is frequently mutated in human cancer. Common mutant p53 (mutp53) isoforms can actively promote cancer through gain-of-function (GOF) mechanisms. We report that mutp53 prolongs TNF-α-induced NF-κB activation in cultured cells and intestinal organoid cultures. Remarkably, when exposed to dextran sulfate sodium, mice harboring a germline p53 mutation develop severe chronic inflammation and persistent tissue damage, and are highly prone to inflammation-associated colon cancer. This mutp53 GOF is manifested by rapid onset of flat dysplastic lesions that progress to invasive carcinoma with mutp53 accumulation and augmented NF-κB activation, faithfully recapitulating features frequently observed in human colitis-associated colorectal cancer (CAC). These findings might explain the early appearance of p53 mutations in human CAC.

Original languageEnglish
Pages (from-to)634-646
Number of pages13
JournalCancer Cell
Volume23
Issue number5
DOIs
StatePublished - 13 May 2013
Externally publishedYes

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