MiR-17/20/93/106 promote hematopoietic cell expansion by targeting sequestosome 1-regulated pathways in mice. Blood

Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.
Blood (Impact Factor: 10.45). 05/2011; 118(4):916-25. DOI: 10.1182/blood-2011-02-336487
Source: PubMed


MicroRNAs (miRNAs) are pivotal for regulation of hematopoiesis but their critical targets remain largely unknown. Here, we show that ectopic expression of miR-17, -20,-93 and -106, all AAAGUGC seed-containing miRNAs, increases proliferation, colony outgrowth and replating capacity of myeloid progenitors and results in enhanced P-ERK levels. We found that these miRNAs are endogenously and abundantly expressed in myeloid progenitors and down-regulated in mature neutrophils. Quantitative proteomics identified sequestosome 1 (SQSTM1), an ubiquitin-binding protein and regulator of autophagy-mediated protein degradation, as a major target for these miRNAs in myeloid progenitors. In addition, we found increased expression of Sqstm1 transcripts during CSF3-induced neutrophil differentiation of 32D-CSF3R cells and an inverse correlation of SQSTM1 protein levels and miR-106 expression in AML samples. ShRNA-mediated silencing of Sqstm1 phenocopied the effects of ectopic miR-17/20/93/106 expression in hematopoietic progenitors in vitro and in mice. Further, SQSTM1 binds to the ligand-activated colony-stimulating factor 3 receptor (CSF3R) mainly in the late endosomal compartment, but not in LC3 positive autophagosomes. SQSTM1 regulates CSF3R stability and ligand-induced mitogen-activated protein kinase signaling. We demonstrate that AAAGUGC seed-containing miRNAs promote cell expansion, replating capacity and signaling in hematopoietic cells by interference with SQSTM1-regulated pathways.

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Available from: Jeroen A A Demmers, Aug 31, 2015
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    • "All together, these data indicate that the effect of p62 deficiency on HP egress is non-cell-autonomous. It has been reported that overexpression of AAAGUGC seedcontaining microRNA promotes cell expansion, replating capacity , and signaling in hematopoietic cells by interfering with p62- regulated pathways in myeloid cell lines and that these changes may reflect the effect of p62 deficiency on HSC and myeloid progenitor mobilization (Meenhuis et al., 2011). To identify whether p62 regulates in vivo hematopoietic cell proliferation, we analyzed the cell cycle status of primary WT and p62-deficient as well as WT hematopoietic cells engrafted in full chimeric WT HM and p62 À/À HM mice. "
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