MiR-17/20/93/106 promote hematopoietic cell expansion by targeting sequestosome 1-regulated pathways in mice.
|Title||MiR-17/20/93/106 promote hematopoietic cell expansion by targeting sequestosome 1-regulated pathways in mice.|
|Publication Type||Journal Article|
|Year of Publication||2011|
|Authors||Meenhuis, A., P. A. van Veelen, H. de Looper, N. van Boxtel, I. J. van den Berge, S. M. Sun, E. Taskesen, P. Stern, A. H. de Ru, A. J. van Adrichem, J. Demmers, M. Jongen-Lavrencic, B. Löwenberg, I. P. Touw, P. A. Sharp, and S. J. Erkeland|
|Date Published||2011 May 31|
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 downregulated 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 signalling. We demonstrate that AAAGUGC seed-containing miRNAs promote cell expansion, replating capacity and signalling in hematopoietic cells by interference with SQSTM1-regulated pathways.