Journal article
Mutant p53 Prolongs NF-kappa B Activation and Promotes Chronic Inflammation and Inflammation-Associated Colorectal Cancer
Cancer Cell, Vol.23(5), pp.634-646
May/2013
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-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.
Details
- Title
- Mutant p53 Prolongs NF-kappa B Activation and Promotes Chronic Inflammation and Inflammation-Associated Colorectal Cancer
- Creators
- Tomer Cooks (null) - 972WIS_INST___122Ioannis S. Pateras (null)Ohad Tarcic (null) - 972WIS_INST___122Hilla Solomon (null) - 972WIS_INST___122Aaron J. Schetter (null)Sylvia Wilder (null) - The Weizmann Institute of ScienceGuillermina Lozano (null)Eli Pikarsky (null)Tim Forshew (null)Nitzan Rozenfeld (null)Noam Harpaz (null)Steven Itzkowitz (null)Curtis C. Harris (null)Varda Rotter (null) - 972WIS_INST___122Vassilis G. Gorgoulis (null)Moshe Oren (null) - 972WIS_INST___122
- Resource Type
- Journal article
- Publication Details
- Cancer Cell, Vol.23(5), pp.634-646; May/2013
- Number of pages
- 13
- Language
- English
- DOI
- https://doi.org/10.1016/j.ccr.2013.03.022
- Grant note
- 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 CorporationWe thank Ori Brenner and Gilgi Friedlander for help with histopathological analysis and expression microarray analysis, respectively. We also thank Ronnie Apte, Elena Voronov, Derek Mann, Neil Perkins, and Yinon Ben-Neriah for helpful advice and suggestions. This work was supported in part by European Commission FP7 funding (INFLACARE agreement number 223151; INSPiRE agreement number 284460), Grant number R37 CA40099 from the National Cancer Institute, a Center of Excellence grant (1779/11) from the Israel Science Foundation, the Dr. Miriam and Sheldon Adelson Medical Research Foundation, and a Center of Excellence grant from the Flight Attendant Medical Research Institute. M.O. is the incumbent of the Andre Lwoff Chair in Molecular Biology. The European Commission is not liable for any use that may be made of the information contained herein. S.I. receives research support and is on the Scientific Advisory Board of Exact Sciences Corporation._ALMAME_DELIMITER_
- Record Identifier
- 993266637803596
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