期刊
CANCER CELL
卷 23, 期 5, 页码 634-646出版社
CELL PRESS
DOI: 10.1016/j.ccr.2013.03.022
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资金
- European Commission [223151, 284460]
- National Cancer Institute [R37 CA40099]
- Center of Excellence grant from the Israel Science Foundation [1779/11]
- Dr. Miriam and Sheldon Adelson Medical Research Foundation
- Center of Excellence grant from the Flight Attendant Medical Research Institute
- Scientific Advisory Board of Exact Sciences Corporation
- Cancer Research UK [11906] Funding Source: researchfish
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-alpha-induced NF-kappa B 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-kappa B 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.
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