MicroRNA miR-24 inhibits erythropoiesis by targeting activin type I receptor ALK4

Abstract

IntroductionErythropoiesis is the complex process during which a fraction of primitive multipotent hematopoietic stem cells become committed to the red cell lineage, undergoing erythroid progenitors (burstforming unit erythroid [BFU-E] and colony-forming unit erythroid [CFU-E]), normoblasts, erythroblasts, reticulocytes, and ultimately differentiating to mature erythrocytes. 1 This process is regulated by various factors such as erythropoietin, testosterone, estrogen, interleukin-3, granulocyte-macrophage colony-stimulating factor, and interleukin-9. 2 Activin, a member of the transforming growth factor-␤ (TGF-␤) superfamily, plays an important role in modulating proliferation and differentiation of erythroid progenitors. [2][3][4] In cooperation with erythropoietin, activin promotes erythroid differentiation by increasing the number of hemoglobin-synthesizing colonies derived from the progenitors CFU-E and enhances the formation of BFU-E. 3,[5][6][7] Activin, like other TGF-␤ superfamily members, signals through 2 types of transmembrane receptors that have intrinsic serine/ threonine kinase activity. 8,9 It binds to type II activin receptor, leading to the recruitment, phosphorylation, and activation of type I activin receptor (ALK4, also known as ActRIB). The activated ALK4 transiently interacts with and then phosphorylates Smad2 and Smad3, which, upon phosphorylation, form a heterocomplex with Co-Smad (Smad4), and the resulting Smad complex is accumulated in the nucleus, binds to the promoter of the target genes, and regulates their expression. 10,11 MicroRNAs (miRNAs) are 21-to 25-nucleotide small regulatory RNAs that modulate gene expression by targeting mRNA for degradation or blocking translation via base-pairing to complementary sites in the 3Ј-untranslated region (3Ј-UTR) of the target mRNAs. 12,13 Hundreds of miRNAs have been identified and they participate in a diverse collection of regulatory events. Investigation of the miRNA expression profile in the course of hematopoietic development suggests their potential regulatory roles in hematopoietic differentiation. 14,15 For example, ectopic expression of miR-181 in hematopoietic progenitor cells increased the proportion of B-lineage cells, whereas miR-142s and miR-223 promote the differentiation to T-lineage but not to B-lineage or myeloid cells. 15 MiR-155 transgenic mice exhibited pre-B cell proliferation and B cell malignancy. 16 Overexpression of miR-150 in hematopoietic stem cells specifically impaired the formation of mature B cells by blocking the transition from the pro-B to the pre-B stage. 17 Although many miRNAs have been implicated in hematopoiesis, few of their targets have been identified. MiR-221 and miR-222, both of which are clustered on the X chromosome and were suggested to inhibit normal erythropoiesis and erythroleukemic cell growth, down-modulated kit receptor expression. 18 In this study, we showed that miR-24 could decrease human ALK4 (hALK4) expression at the mRNA and the protein levels through binding to the 3Ј-untranslated r...

Induction of anion exchanger-1 translation and its opposite roles in the carcinogenesis of gastric cancer cells and differentiation of K562 cells

“…As reported recently, miRNAs are abundant, small non-coding RNAs that mediate sequence-specific, posttranscriptional gene expression by binding to the target 3 0 UTR of mRNA, and have been implicated in the regulation of certain cancer-related processes, including development, differentiation, apoptosis and proliferation (Merkerova et al, 2008;Ruan et al, 2009;Yang et al, 2009). To date, miR-24 has been implicated in the regulation of hematopoietic differentiation and cell proliferation (Lal et al, 2008(Lal et al, , 2009Wang et al, 2008). For example, miR-24 downregulates the expression of human dihydrofolate reductase and expression of miR-24 is upregulated during differentiation of human leukemia cells.…”

MicroRNA 223-dependent expression of LMO2 regulates normal erythropoiesis

“…Several miRNAs participate in the regulation of erythropoiesis: miR-221/222 inhibit normal erythropoiesis and erythroleukemic cell growth down-regulating kit receptor expression, 28 miR-24 hampers erythropoiesis by targeting ALK4 and perturbing activin signaling, 39 miR-320 finely tunes the translational activities of CD71 in reticulocytes, 20 c-Myb and miR-15a form an autoregulatory feedback loop which govern the transition from BFU-E to CFU-E stage. 40 Our results suggest that also miR-223 belongs to a functional set of miRNAs implicated in fine-tuning the expression of key genes to a physiologically relevant level during erythropoiesis.…”

Comprehensive fine mapping of chr12q12-14 and follow-up replication identify activin receptor 1B (ACVR1B) as a muscle strength gene

“…Wang et al 43 showed that miR-24 could decrease human ACVR1B expression at mRNA and protein levels. Published evidence 46 showed that this miR-24 is involved in the inhibition of skeletal muscle differentiation by TGFb.…”