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.

miR-144/451 in hematopoiesis and beyond

“…Thus, in GBM cells, metabolic stress triggers a Cab39/AMPK-mediated positive feedback response between miR-451 and OCT1, which allows tumor cells to quickly adapt to variations of glucose concentrations in the tumor microenvironment. These findings in GBM cells uncover miR-451 as a major player in AMPK signaling, which is consistent with a recent finding in erythroid cells that miR-451 is an important effector that represses Cab39/AMPK activity [46]. The inconsistency is that deficiency of miR-451 in nucleated erythroid cells results in apoptosis, rather than adaptation for survival, in numerous stress conditions, including deprivation of glucose in culture medium ( [46]; unpublished data).…”

“…These findings in GBM cells uncover miR-451 as a major player in AMPK signaling, which is consistent with a recent finding in erythroid cells that miR-451 is an important effector that represses Cab39/AMPK activity [46]. The inconsistency is that deficiency of miR-451 in nucleated erythroid cells results in apoptosis, rather than adaptation for survival, in numerous stress conditions, including deprivation of glucose in culture medium ( [46]; unpublished data). Farnesoid X Receptor (FXR) is a nuclear receptor and controls many aspects of lipid metabolism.…”

“…Over expression of miR-144 or miR-451 enhances maturation of murine erythroleukemic cells, whereas depletion of miR-451 has the opposite effect [29,55]. Surprisingly, in vivo deletion of such abundantly expressed miR-144/451 genes only leads to mild hemolytic anemia [18][19][20]46], partially due to the erythrocytes' impaired capacity to remove reactive oxygen species (ROS) [19]. In animals, deletion of genomic miR-144/451 sequences elevates the level of miR-451 target gene (Ywhaz) product 14-3-3zeta, which sequesters the nuclear factor FoxO3 in the cytoplasm, thereby blocking transcription of anti-oxidant enzymes catalase (Cat) and glutathione peroxidase 1 (Gpx1) by FoxO3 [19].…”

MicroRNA-144 represses gliomas progression and elevates susceptibility to Temozolomide by targeting CAV2 and FGF7

“…Results miR-144 suppressed the proliferation of glioma cells. The miRNAs array analysis from several groups indicated that miR-144 and miR-451a, as anti-tumor miRNAs located in the same cluster, were decreased in different tumor tissues and modulated tumor development [20][21][22] . However, the detail mechanism still remains unclear.…”

“…Therefore identification glioma-related miRNAs and elucidation their effects and regulatory mechanisms have important roles in gliomas therapy. miR-144 located within the miR-144/miR-451a cluster and plays significant roles in tumor progression [20][21][22] . Several reports indicated that miR-144 could suppress tumor cell proliferation and block the cell cycle [23][24][25] .…”