P53 Terminates the Regenerative Fetal-like State After Colitis-associated Injury

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2024 Oct 25

PMID 39453996

Authors

Kimberly Hartl

Safak Bayram

Alexandra Wetzel

Christine Harnack

Manqiang Lin

Anne-Sophie Fischer

Lichao Liu

Giulia Beccaceci

Guido Mastrobuoni

Sabrina Geisberger

Martin Forbes

Benedict J E Monteiro

Martina Macino

Roberto E Flores

Cornelius Engelmann

Hans-Joachim Mollenkopf

Michael Schupp

Frank Tacke

Ashley D Sanders

Stefan Kempa

Hilmar Berger

Michael Sigal

Affiliations

Soon will be listed here.

Abstract

Cells that lack p53 signaling frequently occur in ulcerative colitis (UC) and are considered early drivers in UC-associated colorectal cancer (CRC). Epithelial injury during colitis is associated with transient stem cell reprogramming from the adult, homeostatic to a "fetal-like" regenerative state. Here, we use murine and organoid-based models to study the role of during epithelial reprogramming. We find that p53 signaling is silent and dispensable during homeostasis but strongly up-regulated in the epithelium upon DSS-induced colitis. While in WT cells this causes termination of the regenerative state, crypts that lack remain locked in the highly proliferative, regenerative state long-term. The regenerative state in WT cells requires high Wnt signaling to maintain elevated levels of glycolysis. Instead, deficiency enables Wnt-independent glycolysis due to overexpression of rate-limiting enzyme PKM2. Our study reveals the context-dependent relevance of p53 signaling specifically in the injury-induced regenerative state, explaining the high abundance of clones lacking p53 signaling in UC and UC-associated CRC.

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