Jaako P, Debnath S, Olsson K, Zhang Y, Flygare J, Lindström M S, Bryder D, Karlsson S
Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden.
Molecular Hematology, Lund Stem Cell Center, Lund University, Lund, Sweden.
Leukemia. 2015 Nov;29(11):2221-9. doi: 10.1038/leu.2015.128. Epub 2015 May 19.
Diamond-Blackfan anemia (DBA) is a congenital erythroid hypoplasia caused by haploinsufficiency of genes encoding ribosomal proteins (RPs). Perturbed ribosome biogenesis in DBA has been shown to induce a p53-mediated ribosomal stress response. However, the mechanisms of p53 activation and its relevance for the erythroid defect remain elusive. Previous studies have indicated that activation of p53 is caused by the inhibition of mouse double minute 2 (Mdm2), the main negative regulator of p53, by the 5S ribonucleoprotein particle (RNP). Meanwhile, it is not clear whether this mechanism solely mediates the p53-dependent component found in DBA. To approach this question, we crossed our mouse model for RPS19-deficient DBA with Mdm2(C305F) knock-in mice that have a disrupted 5S RNP-Mdm2 interaction. Upon induction of the Rps19 deficiency, Mdm2(C305F) reversed the p53 response and improved expansion of hematopoietic progenitors in vitro, and ameliorated the anemia in vivo. Unexpectedly, disruption of the 5S RNP-Mdm2 interaction also led to selective defect in erythropoiesis. Our findings highlight the sensitivity of erythroid progenitor cells to aberrations in p53 homeostasis mediated by the 5S RNP-Mdm2 interaction. Finally, we provide evidence indicating that physiological activation of the 5S RNP-Mdm2-p53 pathway may contribute to functional decline of the hematopoietic system in a cell-autonomous manner over time.
钻石黑范贫血（DBA）是一种由核糖体蛋白（RP）编码基因单倍剂量不足引起的先天性红系造血功能低下。已表明DBA中核糖体生物合成紊乱会诱导p53介导的核糖体应激反应。然而，p53激活的机制及其与红系缺陷的相关性仍不清楚。先前的研究表明，5S核糖核蛋白颗粒（RNP）抑制p53的主要负调节因子小鼠双微体2（Mdm2）会导致p53激活。同时，尚不清楚该机制是否单独介导DBA中发现的p53依赖性成分。为了解决这个问题，我们将RPS19缺陷型DBA小鼠模型与具有破坏的5S RNP-Mdm2相互作用的Mdm2（C305F）敲入小鼠进行杂交。在诱导Rps19缺陷后，Mdm2（C305F）逆转了p53反应，改善了体外造血祖细胞的扩增，并改善了体内贫血。出乎意料的是，5S RNP-Mdm2相互作用的破坏也导致了红系造血的选择性缺陷。我们的研究结果突出了红系祖细胞对由5S RNP-Mdm2相互作用介导的p53稳态异常的敏感性。最后，我们提供的证据表明，5S RNP-Mdm2-p53途径的生理激活可能会随着时间的推移以细胞自主方式导致造血系统功能衰退。
