Defective erythroid differentiation in miR-451 mutant mice mediated by 14-3-3ζ

Abstract

Erythrocyte formation occurs throughout life in response to cytokine signaling. We show that microRNA-451 (miR-451) regulates erythropoiesis in vivo. Mice lacking miR-451 display a reduction in hematrocrit, an erythroid differentiation defect, and ineffective erythropoiesis in response to oxidative stress. 14-3-3ζ, an intracellular regulator of cytokine signaling that is repressed by miR-451, is up-regulated in miR-451−/− erythroblasts, and inhibition of 14-3-3ζ rescues their differentiation defect. These findings reveal an essential role of 14-3-3ζ as a mediator of the proerythroid differentiation actions of miR-451, and highlight the therapeutic potential of miR-451 inhibitors.

The Potential Role of miR-451 in Cancer Diagnosis, Prognosis, and Therapy

“…The erythroid differentiation defect was observed in both miR-451 À/À mice and wild-type mice injected with a cholesterol-modified miR-451 antagomir, indicating that miR-451 plays a constitutive role in the differentiation of erythrocytes, rather than a role in embryonic development alone, and that both a chronic and transient loss of miR-451 function elicit the same phenotype (8). In zebrafish, miR-451 accelerates the rate of erythrocyte maturation, partly by repression of gata2, the gene encoding for GATA-2, a prostem cell transcription factor (6).…”

“…At least some protective activities of miR-451 stem from its ability to directly suppress production of 14-3-3z, an intracellular regulator of cytokine signaling proteins that inhibits nuclear accumulation of the transcription factor FoxO3, a positive regulator of erythroid antioxidant genes (8,9). The miR-451/14-3-3z/FoxO3 regulatory axis might have potential implications beyond erythropoiesis.…”

“…5). Broad miRNA expression profiling analyses have recurrently identified miR-144 and miR-451 for their high erythropoietic cell-restricted expression in several species, including zebrafish (4, 6, 7), mice (8)(9)(10), and human (5,11,12). It has been shown that miR-144 regulates a-hemoglobin expression in zebrafish by targeting the erythroid-specific transcription factor KLFD (13).…”

MicroRNA-451 Inhibits Growth of Human Colorectal Carcinoma Cells via Downregulation of Pi3k/Akt Pathway

“…Bioinformatics analysis failed to predict and identify CAB39, LKB1 and AMPK as miR-451 target genes (GBandres et al, 2009;odlewski et al, 2010;Patrick et al, 2010;Li et al, 2011;Tian et al, 2012;Wang et al, 2013). The Western blot results showed that miR-451 over-expression decreased expression of miR-451 target genes, CAB39, LKB1 and AMPK (Figure3).…”

Interplay of transcription factors and microRNAs during embryonic hematopoiesis

“…In addition, the percentage of CD41 + cells was upregulated upon induction of miR-146b ( Figure 5B), suggesting a role of this miRNA in primitive hematopoiesis. Surprisingly, there was no obvious alteration in formation of CD71 high population upon enforced expression of miR-144/451, a previously reported miRNA in the erythroid formation (Patrick et al, 2010). It is possible that sole overexpression of miR-144/451 was not sufficient to induce primitive erythroid fate specification during ESC differentiation.…”