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MiR-144/451 represses the LKB1/AMPK/mTOR pathway to promote red cell precursor survival during recovery from acute anemia.


ABSTRACT: 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.

SUBMITTER: Fang X 

PROVIDER: S-EPMC5830375 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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<i>miR-144/451</i> represses the LKB1/AMPK/mTOR pathway to promote red cell precursor survival during recovery from acute anemia.

Fang Xiao X   Shen Feiyang F   Lechauve Christophe C   Xu Peng P   Zhao Guowei G   Itkow Jacobi J   Wu Fan F   Hou Yaying Y   Wu Xiaohui X   Yu Lingling L   Xiu Huiqing H   Wang Mengli M   Zhang Ruiling R   Wang Fangfang F   Zhang Yanqing Y   Wang Daxin D   Weiss Mitchell J MJ   Yu Duonan D  

Haematologica 20171221 3


The microRNAs <i>miR-144</i> and -<i>451</i> are encoded by a bicistronic gene that is strongly induced during red blood cell formation (erythropoiesis). Ablation of the <i>miR-144/451</i> gene in mice causes mild anemia under baseline conditions. Here we show that <i>miR-144/451</i><sup>-/-</sup> erythroblasts exhibit increased apoptosis during recovery from acute anemia. Mechanistically, <i>miR-144/451</i> depletion increases the expression of the <i>miR-451</i> target mRNA <i>Cab39</i>, which  ...[more]

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