Comparative Oncology Laboratory, Schools of Veterinary Medicine and Medicine, University of California at Davis, Davis, CA, 95616, USA.
College of Life Science and Technology, Huazhong Agricultural University, Wuhan, China.
Cell Death Differ. 2018 Jun;25(6):1118-1130. doi: 10.1038/s41418-017-0029-8. Epub 2018 Jan 22.
Activation of p53-dependent apoptosis is critical for tumor suppression but aberrant activation of p53 also leads to developmental defects and heart failure. Here, we found that Rbm24 RNA-binding protein, a target of p53, regulates p53 mRNA translation. Mechanistically, we found that through binding to p53 mRNA and interaction with translation initiation factor eIF4E, Rbm24 prevents eIF4E from binding to p53 mRNA and inhibits the assembly of translation initiation complex. Importantly, we showed that mice deficient in Rbm24 die in utero due to the endocardial cushion defect in the heart at least in part due to aberrant activation of p53-dependent apoptosis. We also showed that the heart developmental defect in Rbm24-null mice can be partially rescued by p53 deficiency through decreased apoptosis in the heart. Together, we postulate that the p53-Rbm24 loop is critical for the heart development and may be explored for mitigating congenital heart diseases and heart failure.
p53 依赖性细胞凋亡的激活对于肿瘤抑制至关重要，但 p53 的异常激活也会导致发育缺陷和心力衰竭。在这里，我们发现 Rbm24 RNA 结合蛋白是 p53 的靶标，可调节 p53 mRNA 的翻译。在机制上，我们发现 Rbm24 通过与 p53 mRNA 结合并与翻译起始因子 eIF4E 相互作用，防止 eIF4E 与 p53 mRNA 结合并抑制翻译起始复合物的组装。重要的是，我们表明，由于心脏的心内膜垫缺陷，缺乏 Rbm24 的小鼠在子宫内死亡，至少部分原因是 p53 依赖性细胞凋亡的异常激活。我们还表明，通过减少心脏中的细胞凋亡，p53 缺陷可部分挽救 Rbm24 缺失小鼠的心脏发育缺陷。总之，我们假设 p53-Rbm24 循环对于心脏发育至关重要，可能会被探索用于减轻先天性心脏病和心力衰竭。
