Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030;
Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
Proc Natl Acad Sci U S A. 2019 Aug 27;116(35):17429-17437. doi: 10.1073/pnas.1909550116. Epub 2019 Aug 13.
Gastrointestinal (GI) syndrome is a serious side effect and dose-limiting toxicity observed in patients undergoing lower-abdominal radiotherapy. Previous mouse studies show that 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 and thus, normal basal p53 levels and activity. However, due to the lack of p53-mediated transcription, irradiated 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.
胃肠道（GI）综合征是接受下腹部放射治疗的患者中观察到的严重副作用和剂量限制毒性。以前的小鼠研究表明， 基因剂量决定了对 GI 综合征发展的易感性。然而，p53 活性的转化相关性尚未得到解决。在这里，我们使用了一种基因敲入小鼠，其中 p53-Mdm2 负反馈回路在遗传上被破坏。这些小鼠保留了双等位基因，因此，正常的基础 p53 水平和活性。然而，由于缺乏 p53 介导的转录，照射后的 小鼠表现出增强的急性 p53 活性，从而保护它们免受 GI 衰竭。位于 +4 及更高位置的肠隐窝细胞凋亡减少，p21 表达增加，增殖过度，以恢复肠完整性。相应地，用 Mdm2 抑制剂增强野生型小鼠中 p53 活性的药物治疗可预防 GI 毒性而不影响治疗效果。我们的结果表明，短暂破坏 p53-Mdm2 相互作用以增强 p53 活性可能是缓解接受放疗的患者 GI 综合征的可行预防策略。
