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

doi:10.1016/j.ccr.2013.03.022

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

Department of Immunology and Cancer Research

Research output: Contribution to journal › Article › peer-review

356 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 language	American English
Pages (from-to)	634-646
Number of pages	13
Journal	Cancer Cell
Volume	23
Issue number	5
DOIs	https://doi.org/10.1016/j.ccr.2013.03.022
State	Published - 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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Cooks, T., Pateras, I. S., Tarcic, O., Solomon, H., Schetter, A. J., Wilder, S., Lozano, G., Pikarsky, E., Forshew, T., Rozenfeld, N., Harpaz, N., Itzkowitz, S., Harris, C. C., Rotter, V., Gorgoulis, V. G., & Oren, M. (2013). Mutant p53 Prolongs NF-κB Activation and Promotes Chronic Inflammation and Inflammation-Associated Colorectal Cancer. Cancer Cell, 23(5), 634-646. https://doi.org/10.1016/j.ccr.2013.03.022

@article{47ea135a27c34c5ea380c7ce14c7a594,

title = "Mutant p53 Prolongs NF-κB Activation and Promotes Chronic Inflammation and Inflammation-Associated Colorectal Cancer",

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.",

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

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. ",

year = "2013",

month = may,

day = "13",

doi = "10.1016/j.ccr.2013.03.022",

language = "American English",

volume = "23",

pages = "634--646",

journal = "Cancer Cell",

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Cooks, T, Pateras, IS, Tarcic, O, Solomon, H, Schetter, AJ, Wilder, S, Lozano, G, Pikarsky, E, Forshew, T, Rozenfeld, N, Harpaz, N, Itzkowitz, S, Harris, CC, Rotter, V, Gorgoulis, VG & Oren, M 2013, 'Mutant p53 Prolongs NF-κB Activation and Promotes Chronic Inflammation and Inflammation-Associated Colorectal Cancer', Cancer Cell, vol. 23, no. 5, pp. 634-646. https://doi.org/10.1016/j.ccr.2013.03.022

TY - JOUR

T1 - Mutant p53 Prolongs NF-κB Activation and Promotes Chronic Inflammation and Inflammation-Associated Colorectal Cancer

AU - Cooks, Tomer

AU - Pateras, Ioannis S.

AU - Tarcic, Ohad

AU - Solomon, Hilla

AU - Schetter, Aaron J.

AU - Wilder, Sylvia

AU - Lozano, Guillermina

AU - Pikarsky, Eli

AU - Forshew, Tim

AU - Rozenfeld, Nitzan

AU - Harpaz, Noam

AU - Itzkowitz, Steven

AU - Harris, Curtis C.

AU - Rotter, Varda

AU - Gorgoulis, Vassilis G.

AU - Oren, Moshe

N1 - 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.

PY - 2013/5/13

Y1 - 2013/5/13

N2 - 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.

AB - 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.

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DO - 10.1016/j.ccr.2013.03.022

M3 - Article

C2 - 23680148

AN - SCOPUS:84877823153

SN - 1535-6108

VL - 23

SP - 634

EP - 646

JO - Cancer Cell

JF - Cancer Cell

IS - 5

ER -

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

Abstract

Bibliographical note

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