Cross talk between TP53 and c-Myc in the pathophysiology of Diamond-Blackfan anemia: Evidence from RPL11-deficient in vivo and in vitro models
Cross talk between TP53 and c-Myc in the pathophysiology of Diamond-Blackfan anemia: Evidence from RPL11-deficient in vivo and in vitro models
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DOI：
10.1016/j.bbrc.2017.12.019
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发表时间：
2018-01-08
影响因子：
3.1
通讯作者：
Kenmochi, Naoya
中科院分区：
文献类型：
--
作者：
Chakraborty, Anirban;Uechi, Tamayo;Kenmochi, Naoya
在 Diamond-Blackfan 贫血 (DBA) 中发现了编码核糖体蛋白的基因突变，这是一种罕见的遗传性疾病，具有明显的红细胞表型。 TP53 与 DBA 的病理生理学有关，核糖体蛋白 (RP) L11 在 TP53 反应中发挥着至关重要的作用。有趣的是，RPL11 还控制 c-Myc 的转录活性，c-Myc 是一种正调节核糖体生物发生的癌蛋白。在本研究中，我们分析了 rplli 耗竭对斑马鱼红细胞生成和核糖体生物发生的影响。正如预期的那样，Rp111 缺陷的斑马鱼表现出核糖体生物发生缺陷和贫血表型。然而，Tp53 的共同抑制并没有减轻这些鱼的红细胞再生障碍。接下来，我们探讨了 c-Myc 在 RPL11 缺陷细胞和动物模型中的作用。 c-Myc 及其靶核仁蛋白在 Rp111 缺陷的斑马鱼头部区域表现出上调和定位增加，其中形态异常和 tp53 表达更加明显。有趣的是，在RPL11突变的DBA患者的血细胞中，核糖体的生物合成存在缺陷，但c-Myc及其靶核仁蛋白的表达水平没有变化。结果表明，RPL11 缺陷会激活 c-Myc 靶核仁蛋白的合成，从而触发 p53 反应。这些结果进一步证明 Tp53 的诱导介导与 RPL11 缺陷相关的形态缺陷，但不介导红细胞缺陷。 (C) 2017 Elsevier Inc. 保留所有权利。
Mutations in genes encoding ribosomal proteins have been identified in Diamond-Blackfan anemia (DBA), a rare genetic disorder that presents with a prominent erythroid phenotype. TP53 has been implicated in the pathophysiology of DBA with ribosomal protein (RP) L11 playing a crucial role in the TP53 response. Interestingly, RPL11 also controls the transcriptional activity of c-Myc, an oncoprotein that positively regulates ribosome biogenesis. In the present study, we analyzed the consequences of rplli depletion on erythropoiesis and ribosome biogenesis in zebrafish. As expected, Rp111-deficient zebrafish exhibited defects in ribosome biogenesis and an anemia phenotype. However, co-inhibition of Tp53 did not alleviate the erythroid aplasia in these fish. Next, we explored the role of c-Myc in RPL11-deficient cellular and animal models. c-Myc and its target nucleolar proteins showed upregulation and increased localization in the head region of Rp111-deficient zebrafish, where the morphological abnormalities and tp53 expression were more pronounced. Interestingly, in blood cells derived from DBA patients with mutations in RPL11, the biogenesis of ribosomes was defective, but the expression level of c-Myc and its target nucleolar proteins was unchanged. The results suggest a model whereby RPL11 deficiency activates the synthesis of c-Myc target nucleolar proteins, which subsequently triggers a p53 response. These results further demonstrate that the induction of Tp53 mediates the morphological, but not erythroid, defects associated with RPL11 deficiency. (C) 2017 Elsevier Inc. All rights reserved.