Mutant p53 prolongs NF-κB activation and promotes chronic inflammation and inflammation-associated colorectal cancer.

Cooks T, Pateras IS, Tarcic O, Solomon H, Schetter AJ, Wilder S, Lozano G, Pikarsky E, Forshew T, Rosenfeld N, Rozenfeld N, Harpaz N, Itzkowitz S, Harris CC, Rotter V, Gorgoulis VG, Oren M
Cancer Cell. 2013 23 (5): 634-46

PMID: 23680148 · PMCID: PMC3657134 · DOI:10.1016/j.ccr.2013.03.022

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.

Copyright © 2013 Elsevier Inc. All rights reserved.

MeSH Terms (17)

Animals Azoxymethane Colitis Colon Colorectal Neoplasms Dextran Sulfate DNA Damage Genetic Predisposition to Disease Histones Humans Mice Mice, Inbred C57BL NF-kappa B Nitric Oxide Synthase Type II Protein Isoforms Tumor Necrosis Factor-alpha Tumor Suppressor Protein p53

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