Abstract
Gastrointestinal (GI) syndrome is a serious side effect and doselimiting toxicity observed in patients undergoing lower-abdominal radiotherapy. Previous mouse studies show that p53 gene dosage determines susceptibility to GI syndrome development. However, the translational relevance of p53 activity has not been addressed. Here, we used a knock-in mouse in which the p53-Mdm2 negative feedback loop is genetically disrupted. These mice retain biallelic p53 and thus, normal basal p53 levels and activity. However, due to the lack of p53-mediated Mdm2 transcription, irradiated Mdm2P2/P2 mice exhibit enhanced acute p53 activity, which protects them from GI failure. Intestinal crypt cells residing in the +4 and higher positions exhibit decreased apoptosis, increased p21 expression, and hyperproliferation to reinstate intestinal integrity. Correspondingly, pharmacological augmentation of p53 activity in wild-type mice with an Mdm2 inhibitor protects against GI toxicity without affecting therapeutic outcome. Our results suggest that transient disruption of the p53-Mdm2 interaction to enhance p53 activity could be a viable prophylactic strategy for alleviating GI syndrome in patients undergoing radiotherapy.
Original language | English (US) |
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Pages (from-to) | 17429-17437 |
Number of pages | 9 |
Journal | Proceedings of the National Academy of Sciences of the United States of America |
Volume | 116 |
Issue number | 35 |
DOIs | |
State | Published - Aug 27 2019 |
Keywords
- Gastrointestinal syndrome
- P21
- RG7112
- Shielded body radiation
- Stem cells
ASJC Scopus subject areas
- General
MD Anderson CCSG core facilities
- Genetically Engineered Mouse Facility
- Research Animal Support Facility
- Tissue Biospecimen and Pathology Resource