miR-144/451 represses the LKB1/AMPK/mTOR pathway to promote red cell precursor survival during recovery from acute anemia.
miR-144/451 represses the LKB1/AMPK/mTOR pathway to promote red cell precursor survival during recovery from acute anemia.
复制标题
miR-144/451抑制LKB1/AMPK/mTOR通路以促进急性贫血恢复期间红细胞前体存活
DOI：
10.3324/haematol.2017.177394
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发表时间：
2018-03
期刊：
影响因子：
10.1
通讯作者：
Yu D
中科院分区：
文献类型：
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作者：
Fang X;Shen F;Lechauve C;Xu P;Zhao G;Itkow J;Wu F;Hou Y;Wu X;Yu L;Xiu H;Wang M;Zhang R;Wang F;Zhang Y;Wang D;Weiss MJ;Yu D
MicroRNAs miR-144和-451由一个双顺反子基因编码，该基因在红细胞形成(红细胞生成)过程中被强烈诱导。在基线条件下，去除小鼠的miR-144/451基因会导致轻度贫血。在这里，我们展示了MIR144/451MIR144/451MIR144/451MIR144/451MIR144/451MIR144/451MIR144−/−红细胞在急性贫血恢复过程中表现出更多的凋亡率。从机制上讲，miR-144/451缺失增加了miR-451目标mRNA Cab39的表达，该基因编码丝氨酸苏氨酸激酶LKB1的辅助因子。在红细胞生成应激过程中，MIR144/451LBP的−/−蛋白异常增加，激活了LKB1及其下游的AMPK/mTOR效应通路。通过药物或shRNAs抑制这一途径可提高突变红细胞的存活率。因此，miR-144/451通过抑制Cab39/AMPK/mTOR促进急性贫血的恢复。我们的发现表明，miR-144/451在红细胞需求急剧增加的病理状态下是红细胞的关键保护者，包括急性失血和溶血性贫血。
The microRNAs miR-144 and -451 are encoded by a bicistronic gene that is strongly induced during red blood cell formation (erythropoiesis). Ablation of the miR-144/451 gene in mice causes mild anemia under baseline conditions. Here we show that miR-144/451−/− erythroblasts exhibit increased apoptosis during recovery from acute anemia. Mechanistically, miR-144/451 depletion increases the expression of the miR-451 target mRNA Cab39, which encodes a co-factor for the serine-threonine kinase LKB1. During erythropoietic stress, miR-144/451−/− erythroblasts exhibit abnormally increased Cab39 protein, which activates LKB1 and its downstream AMPK/mTOR effector pathway. Suppression of this pathway via drugs or shRNAs enhances survival of the mutant erythroblasts. Thus, miR-144/451 facilitates recovery from acute anemia by repressing Cab39/AMPK/mTOR. Our findings suggest that miR-144/451 is a key protector of erythroblasts during pathological states associated with dramatically increased erythropoietic demand, including acute blood loss and hemolytic anemia.