Rosa A, Ballarino M, Sorrentino A, Sthandier O, De Angelis FG, Marchioni M et al.. The interplay between the master transcription factor PU.1 and miR-424 regulates human monocyte/macrophage differentiation. Proc Natl Acad Sci USA 104: 19849-19854

Institute Pasteur Cenci-Bolognetti, Department of Genetics and Molecular Biology, Institute of Molecular Biology and Pathology, and Department of Cellular Biotechnologies and Hematology, University of Rome "La Sapienza", Rome, Italy.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 01/2008; 104(50):19849-54. DOI: 10.1073/pnas.0706963104
Source: PubMed


We describe a pathway by which the master transcription factor PU.1 regulates human monocyte/macrophage differentiation. This includes miR-424 and the transcriptional factor NFI-A. We show that PU.1 and these two components are interlinked in a finely tuned temporal and regulatory circuitry: PU.1 activates the transcription of miR-424, and this up-regulation is involved in stimulating monocyte differentiation through miR-424-dependent translational repression of NFI-A. In turn, the decrease in NFI-A levels is important for the activation of differentiation-specific genes such as M-CSFr. In line with these data, both RNAi against NFI-A and ectopic expression of miR-424 in precursor cells enhance monocytic differentiation, whereas the ectopic expression of NFI-A has an opposite effect. The interplay among these three components was demonstrated in myeloid cell lines as well as in human CD34+ differentiation. These data point to the important role of miR-424 and NFI-A in controlling the monocyte/macrophage differentiation program.

Download full-text


Available from: Alessandro Rosa, May 20, 2014
  • Source
    • "The role of miR-424 has been investigated in several types of physiological and pathological conditions, which revealed the diverse function of miR-424 in different situations. It was reported that miR-424 was implicated in maintaining the physiology of vascular remodeling and angiogenesis24, remodeling of the epithelium in the mammary gland25, protecting against permanent focal cerebral ischemia injury26, promoting differentiation of monocytes27 and skeletal muscle-derived progenitor cells28. Recently, an interesting study showed that miR-424 was involved in APLN-dependent miRNA-FGF signaling axis needed for the maintenance of pulmonary vascular homeostasis29. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Resistance to anoikis and Epithelial-mesenchymal transition (EMT) are two processes critically involved in cancer metastasis. In this study, we demonstrated that after anchorage deprival, hepatocellular carcinoma (HCC) cells not only resisted anoikis, but also exhibited EMT process. Microarray expression profiling revealed that expression of miR-424-5p was significantly decreased in anoikis-resistant HCC cells. Ectopic overexpression of miR-424-5p was sufficient to reverse resistance to anoikis, block EMT process and inhibit malignant behaviors of HCC cells. Target analysis showed that a potent β-catenin inhibitor, ICAT/CTNNBIP1 was a direct target of miR-424-5p. Further study demonstrated that miR-424-5p reversed resistance to anoikis and EMT of HCCs by directly targeting ICAT and further maintaining the E-cadherin/β-catanin complex on the cellular membrance. In vivo study further demonstrated that miR-424-5p significantly inhibited the tumorigenicity of HCC cells in nude mice. Clinical investigation demonstrated that miR-424-5p was significantly downregulated in HCC tissues compared with that of the non-cancerous liver tissues, and this decreased expression of miR-424-5p was significantly correlated with higher pathological grades and more advanced TNM stages. Therefore, aberrant expression of miR-424-5p is critically involved in resistance to anoikis and EMT during the metastatic process of HCC, and its downregulation significantly contributes to liver cancer progression.
    Full-text · Article · Sep 2014 · Scientific Reports
  • Source
    • "Recent evidence suggests that microRNAs (miRNAs or miRs) are important regulators of normal hematopoietic differentiation [8-13]. Transcription factors such as PU.1 regulate a number of miRNAs, and correspondingly, miRNAs also regulate transcription factor expression in normal hematopoiesis [11,12,14,15]. For example, miR-223 and the transcription factors CEPBA, PU.1, NFI-A and E2F2 contribute to a regulatory circuit that controls normal granulopoiesis [16,17]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In acute myeloid leukemia (AML) and blast crisis (BC) chronic myeloid leukemia (CML) normal differentiation is impaired. Differentiation of immature stem/progenitor cells is critical for normal blood cell function. MicroRNAs (miRNAs or miRs) are small non-coding RNAs that interfere with gene expression by degrading messenger RNAs (mRNAs) or blocking protein translation. Aberrant miRNA expression is a feature of leukemia and miRNAs also play a significant role in normal hematopoiesis and differentiation. We have identified miRNAs differentially expressed in AML and BC CML and identified a new role for miR-150 in myeloid differentiation. Expression of miR-150 is low or absent in BC CML and AML patient samples and cell lines. We have found that expression of miR-150 in AML cell lines, CD34+ progenitor cells from healthy individuals, and primary BC CML and AML patient samples at levels similar to miR-150 expression in normal bone marrow promotes myeloid differentiation of these cells. MYB is a direct target of miR-150, and we have identified that the observed phenotype is partially mediated by MYB. In AML cell lines, differentiation of miR-150 expressing cells occurs independently of retinoic acid receptor α (RARA) signaling. High-throughput gene expression profiling (GEP) studies of the AML cell lines HL60, PL21, and THP-1 suggest that activation of CEPBA, CEBPE, and cytokines associated with myeloid differentiation in miR-150 expressing cells as compared to control cells contributes to myeloid differentiation. These data suggest that miR-150 promotes myeloid differentiation, a previously uncharacterized role for this miRNA, and that absent or low miR-150 expression contributes to blocked myeloid differentiation in acute leukemia cells.
    Full-text · Article · Sep 2013 · PLoS ONE
  • Source
    • "Another transcription factor related to monocyte differentiation, PU.1, activates transcription of miR-424. Upregulation of miR-424 stimulates monocyte differentiation [122]. Studies by Junker et al. conducted in active MS lesions identified three upregulated miRNAs: miR-155, miR-326, and miR-34a that target the same transcript—CD47 mRNA [119]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: MicroRNAs are relatively recently discovered class of small noncoding RNAs, which function as important regulators of gene expression. They fine-tune protein expression either by translational inhibition or mRNA degradation. MicroRNAs act as regulators of diverse cellular processes, such as cell differentiation, proliferation, and apoptosis. Their defective biogenesis or function has been identified in various pathological conditions, like inflammation, neurodegeneration, or autoimmunity. Multiple sclerosis is one of the predominated debilitating neurological diseases affecting mainly young adults. It is a multifactorial disorder of as yet unknown aetiology. As far, it is suggested that interplay between genetic and environmental factors is responsible for MS pathogenesis. The role of microRNAs in this pathology is now extensively studied. Here, we want to review the current knowledge of microRNAs role in multiple sclerosis.
    Full-text · Article · Jul 2013 · Mediators of Inflammation
Show more