Abstract
M-CSF regulates the production, survival, and function of monocytes and macrophages. The MAPKs ERK1/2 are key elements for signal integration downstream of the M-CSFR, and their sustained activation is essential for macrophage differentiation. In this study, we sought to isolate genes whose induction by M-CSF is dependent on persistent MAPK activation, thereby being possibly involved in the commitment of myeloid progenitors to macrophage differentiation. Following SSH between cDNA libraries from FD-Fms cells stimulated by M-CSF for 8 h in the presence or the absence of the MEK inhibitor U0126, we isolated DUSP5. DUSP5 expression is induced by M-CSF in various myeloid cells and acts as a specific negative-feedback regulator of ERK1/2. In FD-Fms cells that proliferate and differentiate toward macrophages in response to M-CSF, overexpression of DUSP5 increased M-CSF-dependent proliferation and strongly decreased differentiation. Similarly, overexpression of DUSP5 in the multipotent EGER-Fms cells not only significantly increased M-CSF-induced proliferation and prevented macrophage differentiation but also favored granulocytic differentiation. Altogether, experiments demonstrated that DUSP5 is implicated in M-CSF signaling and suggested that it may influence myeloid cell fate.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ADAM Proteins / biosynthesis
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ADAM Proteins / genetics
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Animals
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Antigens, CD / biosynthesis
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Antigens, CD / genetics
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Butadienes / pharmacology
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Cells, Cultured / cytology
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Cells, Cultured / drug effects
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Dual-Specificity Phosphatases / biosynthesis
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Dual-Specificity Phosphatases / genetics
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Dual-Specificity Phosphatases / physiology*
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Gene Expression Regulation / drug effects
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Humans
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MAP Kinase Signaling System / drug effects
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Macrophage Colony-Stimulating Factor / pharmacology*
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Macrophages / cytology*
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Membrane Proteins / biosynthesis
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Membrane Proteins / genetics
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Mice
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / metabolism
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Multipotent Stem Cells / drug effects*
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Myelopoiesis / drug effects*
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Myelopoiesis / genetics
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Nitriles / pharmacology
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Osteopontin / biosynthesis
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Osteopontin / genetics
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Phosphorylation / drug effects
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Protein Processing, Post-Translational / drug effects
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Receptor, Macrophage Colony-Stimulating Factor / drug effects
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Receptor, Macrophage Colony-Stimulating Factor / genetics
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Recombinant Fusion Proteins / drug effects
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Recombinant Fusion Proteins / physiology
Substances
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Antigens, CD
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Butadienes
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Membrane Proteins
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Nitriles
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Recombinant Fusion Proteins
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Spp1 protein, mouse
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U 0126
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Osteopontin
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Macrophage Colony-Stimulating Factor
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Receptor, Macrophage Colony-Stimulating Factor
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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DUSP5 protein, human
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Dual-Specificity Phosphatases
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Dusp5 protein, mouse
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ADAM Proteins
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Adam8 protein, mouse