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miR-144/451 represses the LKB1/AMPK/mTOR pathway to promote red cell precursor survival during recovery from acute anemia
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 apopto...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Ferrata Storti Foundation
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830375/ https://www.ncbi.nlm.nih.gov/pubmed/29269522 http://dx.doi.org/10.3324/haematol.2017.177394 |
Sumario: | 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. |
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