Defective erythropoiesis in a mouse model of reduced Fbxo7 expression due to decreased p27 expression.
Defective erythropoiesis in a mouse model of reduced Fbxo7 expression due to decreased p27 expression.
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DOI：
10.1002/path.4571
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发表时间：
2015-10
期刊：
影响因子：
--
通讯作者：
Laman H
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文献类型：
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作者：
Randle SJ;Nelson DE;Patel SP;Laman H
在红细胞生成的最后阶段，血统受限的祖细胞经过三到五次细胞分裂成熟，最终退出细胞周期，失去包括线粒体和细胞核在内的大多数细胞器。最近在人类群体中的全基因组关联研究已经将Fbxo7附近或内部的几个SNP与红细胞表型相关联。Fbxo7编码一种多功能的F-box蛋白，可与p27结合并参与选择性有丝分裂。一个SNP导致氨基酸替代(Met115Ile)，并与较小的红细胞相关。我们发现Fbxo7不太常见的IIe115等位基因与p27的结合效率较低，表达该等位基因的细胞增殖速度快于表达Met115的细胞。我们发现，Fbxo7表达降低的红白血病细胞株不能稳定p27水平，退出细胞周期，并产生血红蛋白。此外，Fbxo7表达不足的小鼠由于红细胞数量减少而贫血，这与较低的p27水平、高于2N DNA含量的晚期红细胞数量增加以及终末分化过程中的有丝分裂延迟有关。总而言之，这些数据支持Fbxo7在红细胞生成过程中的重要生理和细胞周期调节作用。©2015作者。《病理学杂志》由John Wiley&Sons Ltd代表大不列颠和爱尔兰病理学会出版。
During the final stages of erythropoiesis, lineage-restricted progenitors mature over three to five cell divisions, culminating with withdrawal from the cell cycle and the loss of most organelles, including mitochondria and nuclei. Recent genome-wide association studies in human populations have associated several SNPs near or within FBXO7 with erythrocyte phenotypes. Fbxo7 encodes a multi-functional F-box protein known to bind p27 and participate in selective mitophagy. One SNP causes an amino acid substitution (Met115Ile) and is associated with smaller erythrocytes. We find that the less common IIe115 allele of Fbxo7 binds less efficiently to p27, and cells expressing this allele proliferate faster than cells expressing Met115. We show that an erythroleukaemic cell line with reduced Fbxo7 expression fails to stabilize p27 levels, exit the cell cycle, and produce haemoglobin. In addition, mice deficient in Fbxo7 expression are anaemic due to a reduction in erythrocyte numbers, and this is associated with lower p27 levels, increased numbers of late-stage erythroblasts with greater than 2N DNA content, and delayed mitophagy during terminal differentiation. Collectively, these data support an important physiological, cell cycle regulatory role for Fbxo7 during erythropoiesis. © 2015 Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.