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.
Copyright © 2013 Elsevier Inc. All rights reserved.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Azoxymethane
-
Colitis / chemically induced
-
Colitis / complications
-
Colitis / genetics
-
Colon / metabolism
-
Colon / pathology
-
Colorectal Neoplasms / etiology
-
Colorectal Neoplasms / genetics*
-
Colorectal Neoplasms / metabolism
-
Colorectal Neoplasms / pathology
-
DNA Damage
-
Dextran Sulfate
-
Genetic Predisposition to Disease
-
Histones / metabolism
-
Humans
-
Mice
-
Mice, Inbred C57BL
-
NF-kappa B / metabolism
-
NF-kappa B / physiology*
-
Nitric Oxide Synthase Type II / metabolism
-
Protein Isoforms / physiology
-
Tumor Necrosis Factor-alpha / metabolism
-
Tumor Necrosis Factor-alpha / physiology
-
Tumor Suppressor Protein p53 / genetics*
-
Tumor Suppressor Protein p53 / physiology
Substances
-
Histones
-
NF-kappa B
-
Protein Isoforms
-
Tumor Necrosis Factor-alpha
-
Tumor Suppressor Protein p53
-
gamma-H2AX protein, mouse
-
Dextran Sulfate
-
Nitric Oxide Synthase Type II
-
Nos2 protein, mouse
-
Azoxymethane