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| Item Type: | Article |
|---|---|
| Title: | p53 terminates the regenerative fetal-like state after colitis-associated injury |
| Creators Name: | Hartl, K., Bayram, Ş., Wetzel, A., Harnack, C., Lin, M., Fischer, A.S., Liu, L., Beccacec, G., Mastrobuoni, G., Geisberger, S., Forbes, M., Monteiro, B.J.E., Macino, M., Flores, R.E., Engelmann, C., Mollenkopf, H.J., Schupp, M., Tacke, F., Sanders, A.D., Kempa, S., Berger, H. and Sigal, M. |
| 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 Trp53 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 Trp53 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, Trp53 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. |
| Keywords: | Animal Disease Models, Colitis, Glycolysis, Intestinal Mucosa, Organoids, Regeneration, Signal Transduction, Tumor Suppressor Protein p53, Ulcerative Colitis, Wnt Signaling Pathway, Animals, Mice |
| Source: | Science Advances |
| ISSN: | 2375-2548 |
| Publisher: | American Association for the Advancement of Science |
| Volume: | 10 |
| Number: | 43 |
| Page Range: | eadp8783 |
| Date: | 25 October 2024 |
| Official Publication: | https://doi.org/10.1126/sciadv.adp8783 |
| PubMed: | View item in PubMed |
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