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

Abstract

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>^-/- 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 encodes a co-factor for the serine-threonine kinase LKB1. During erythropoietic stress, <i>miR-144/451</i>^-/- erythroblasts exhibit abnormally increased Cab39 protein, which activates LKB1 and its downstream AMPK/mTOR effector pathway. Suppression of this pathway <i>via</i> drugs or shRNAs enhances survival of the mutant erythroblasts. Thus, <i>miR-144/451</i> facilitates recovery from acute anemia by repressing Cab39/AMPK/mTOR. Our findings suggest that <i>miR-144/451</i> is a key protector of erythroblasts during pathological states associated with dramatically increased erythropoietic demand, including acute blood loss and hemolytic anemia.