title: Mutant p53 prolongs NF-κB activation and promotes chronic inflammation and inflammation-associated colorectal cancer.
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.
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Tomer
authors.initials: T
authors.lastname: Cooks
authors.forename: Ioannis S
authors.initials: IS
authors.lastname: Pateras
authors.forename: Ohad
authors.initials: O
authors.lastname: Tarcic
authors.forename: Hilla
authors.initials: H
authors.lastname: Solomon
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Schetter
authors.forename: Sylvia
authors.initials: S
authors.lastname: Wilder
authors.forename: Guillermina
authors.initials: G
authors.lastname: Lozano
authors.forename: Eli
authors.initials: E
authors.lastname: Pikarsky
authors.forename: Tim
authors.initials: T
authors.lastname: Forshew
authors.forename: Nitzan
authors.initials: N
authors.lastname: Rosenfeld
authors.forename: Nitzan
authors.initials: N
authors.lastname: Rozenfeld
authors.forename: Noam
authors.initials: N
authors.lastname: Harpaz
authors.forename: Steven
authors.initials: S
authors.lastname: Itzkowitz
authors.forename: Curtis C
authors.initials: CC
authors.lastname: Harris
authors.forename: Varda
authors.initials: V
authors.lastname: Rotter
authors.forename: Vassilis G
authors.initials: VG
authors.lastname: Gorgoulis
authors.forename: Moshe
authors.initials: M
authors.lastname: Oren
mesh_terms: D000818:Animals; D001397:Azoxymethane; D003092:Colitis / Q000139:chemically induced / Q000150:complications / Q000235:genetics; D003106:Colon / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004249:DNA Damage; D016264:Dextran Sulfate; D020022:Genetic Predisposition to Disease; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D020033:Protein Isoforms / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000502:physiology
chemical_list: D006657:Histones; D016328:NF-kappa B; D020033:Protein Isoforms; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; C475961:gamma-H2AX protein, mouse; D016264:Dextran Sulfate; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D001397:Azoxymethane