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

Tomer Cooks, Ioannis S. Pateras, Ohad Tarcic, Hilla Solomon, Aaron J. Schetter, Sylvia Wilder, Guillermina Lozano, Eli Pikarsky, Tim Forshew, Nitzan Rozenfeld, Noam Harpaz, Steven Itzkowitz, Curtis C. Harris, Varda Rotter, Vassilis G. Gorgoulis, Moshe Oren*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

369 Scopus citations

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.

Original languageAmerican English
Pages (from-to)634-646
Number of pages13
JournalCancer Cell
Volume23
Issue number5
DOIs
StatePublished - 13 May 2013

Bibliographical note

Funding Information:
We 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.

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