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| Item Type: | Article |
|---|---|
| Title: | p53 terminates the regenerative fetal-like state after colitis-associated injury |
| Creators: |
Hartl, K.  ORCID: https://orcid.org/0000-0002-2965-0512, Bayram, Ş. ORCID: https://orcid.org/0009-0009-5245-5473, Wetzel, A., Harnack, C., Lin, M. ORCID: https://orcid.org/0000-0003-4093-9277, Fischer, A.S. ORCID: https://orcid.org/0000-0002-2176-1779, Liu, L. ORCID: https://orcid.org/0000-0002-9553-5475, Beccacec, G. ORCID: https://orcid.org/0000-0002-6453-3725, Mastrobuoni, G. ORCID: https://orcid.org/0000-0003-4509-1295, Geisberger, S. ORCID: https://orcid.org/0000-0001-6477-1312, Forbes, M. ORCID: https://orcid.org/0000-0001-7775-8352, Monteiro, B.J.E. ORCID: https://orcid.org/0000-0001-9718-2776, Macino, M. ORCID: https://orcid.org/0000-0002-8730-9005, Flores, R.E. ORCID: https://orcid.org/0000-0001-6500-8407, Engelmann, C., Mollenkopf, H.J. ORCID: https://orcid.org/0000-0003-1167-4783, Schupp, M. ORCID: https://orcid.org/0000-0003-3720-1052, Tacke, F. ORCID: https://orcid.org/0000-0001-6206-0226, Sanders, A.D. ORCID: https://orcid.org/0000-0003-3945-0677, Kempa, S. ORCID: https://orcid.org/0000-0002-0696-9299, Berger, H. ORCID: https://orcid.org/0000-0002-6304-4946 and Sigal, M. ORCID: https://orcid.org/0000-0003-4772-0761
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| 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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