Transient enhancement of p53 activity protects from radiation-induced gastrointestinal toxicity

• Published in: Proceedings of the National Academy of Sciences - PNAS 2019-08, Vol.116 (35), p.17429-17437
• Main Authors: Pant, Vinod, Xiong, Shunbin, Wasylishen, Amanda R., Larsson, Connie A., Aryal, Neeraj K., Chau, Gilda, Tailor, Ramesh C., Lozano, Guillermina
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Apoptosis - genetics; Biological Sciences; Cell Line, Tumor; Disease Models, Animal; Disruption; Feedback loops; Gastrointestinal Diseases - etiology; Gastrointestinal Diseases - metabolism; Gastrointestinal Diseases - mortality; Gastrointestinal Diseases - pathology; Gastrointestinal Tract - metabolism; Gastrointestinal Tract - pathology; Gastrointestinal Tract - radiation effects; Gene dosage; Humans; Intestine; MDM2 protein; Mice; Mice, Knockout; Models, Biological; Negative feedback; p53 Protein; Radiation; Radiation effects; Radiation Injuries - genetics; Radiation Injuries - metabolism; Radiation Injuries - mortality; Radiation Injuries - pathology; Radiation Injuries, Experimental; Radiation therapy; Radiation, Ionizing; ras Proteins - genetics; ras Proteins - metabolism; Toxicity; Transcription; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1909550116

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.