IRFs [IFN (interferon) regulatory factors] constitute a family of transcription factors involved in IFN signalling and in the development and differentiation of the immune system. IRF-2 has generally been described as an antagonist of IRF-1-mediated transcription of IFN and IFN-inducible genes; however, it has been recently identified as a transcriptional activator of some genes, such as those encoding histone H4, VCAM-1 (vascular cell adhesion molecule-1) and Fas ligand. Biologically, IRF-2 plays an important role in cell growth regulation and has been shown to be a potential oncogene. Studies in knock-out mice have also implicated IRF-2 in the differentiation and functionality of haematopoietic cells. Here we show that IRF-2 expression in a myeloid progenitor cell line leads to reprogramming of these cells towards the megakaryocytic lineage and enables them to respond to thrombopoietin, as assessed by cell morphology and expression of specific differentiation markers. Up-regulation of transcription factors involved in the development of the megakaryocytic lineage, such as GATA-1, GATA-2, FOG-1 (friend of GATA-1) and NF-E2 (nuclear factor-erythroid-2), and transcriptional stimulation of the thrombopoietin receptor were also demonstrated. Our results provide evidence for a key role for IRF-2 in the induction of a programme of megakaryocytic differentiation, and reveal a remarkable functional diversity of this transcription factor in the regulation of cellular responses.
- gene expression
- gene transcription
- haematopoietic differentiation
- interferon regulatory factor
- transcription factor
↵1 These authors contributed equally to this work.
Abbreviations used: AP-1, activator protein-1; EMSA, electrophoretic mobility shift assay; FOG, friend of GATA; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; G-CSF, granulocytic colony-stimulating factor; IFN, interferon; IL-3, interleukin-3; ISRE, interferon-stimulated response element; IRF, interferon regulatory factor; Mk, megakaryocyte; NF-E2, nuclear factor-erythroid-2; PE, phycoerythrin; PF4, platelet factor 4; RT-PCR, reverse transcription–PCR; SBE, STAT-binding element; STAT, signal transducers and activators of transcription; siRNA, small interfering RNA; TPO, thrombopoietin; TPO-R, thrombopoietin receptor; VCAM-1, vascular cell adhesion molecule-1.
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