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

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, whe...

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Veröffentlicht in:Cancer cell 2013-05, Vol.23 (5), p.634-646
Hauptverfasser: Cooks, Tomer, Pateras, Ioannis S., Tarcic, Ohad, Solomon, Hilla, Schetter, Aaron J., Wilder, Sylvia, Lozano, Guillermina, Pikarsky, Eli, Forshew, Tim, Rozenfeld, Nitzan, Harpaz, Noam, Itzkowitz, Steven, Harris, Curtis C., Rotter, Varda, Gorgoulis, Vassilis G., Oren, Moshe
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Sprache:eng
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Zusammenfassung: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. •Mutant p53 promotes chronic NF-κB activation•Mutant p53 promotes persistent tissue damage and extended inflammation•Mutant p53 mice are highly prone to inflammation-associated colorectal cancer•DSS-treated mutant p53 mice faithfully recapitulate human colitis-associated cancer
ISSN:1535-6108
1878-3686
DOI:10.1016/j.ccr.2013.03.022