Περίληψη:
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. © 2013 Elsevier Inc.
Συγγραφείς:
Cooks, T.
Pateras, I.
Tarcic, O.
Solomon, H.
Schetter, A.
Wilder, S.
Lozano, G.
Pikarsky, E.
Forshew, T.
Rozenfeld, N.
Harpaz, N.
Itzkowitz, S.
Harris, C.
Rotter, V.
Gorgoulis, V.
Oren, M.
Λέξεις-κλειδιά:
dextran sulfate; immunoglobulin enhancer binding protein; protein p53, article; cell culture; chromatin immunoprecipitation; chronic inflammation; colitis; colorectal cancer; disease association; disease severity; enzyme activation; human; human cell; inflammation; invasive carcinoma; mouse; nonhuman; nucleotide sequence; priority journal; real time polymerase chain reaction; tissue injury
