Differential utilization of Ras signaling pathways by macrophage colony-stimulating factor (CSF) and granulocyte-macrophage CSF receptors during macrophage differentiation.
Fiche publication
Date publication
juillet 1998
Journal
Molecular and cellular biology
Auteurs
Membres identifiés du Cancéropôle Est :
Dr GUIDEZ Fabien
Tous les auteurs :
Guidez F, Li AC, Horvai A, Welch JS, Glass CK
Lien Pubmed
Résumé
Granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) independently stimulate the proliferation and differentiation of macrophages from bone marrow progenitor cells. Although the GM-CSF and M-CSF receptors are unrelated, both couple to Ras-dependent signal transduction pathways, suggesting that these pathways might account for common actions of GM-CSF and M-CSF on the expression of macrophage-specific genes. To test this hypothesis, we have investigated the mechanisms by which GM-CSF and M-CSF regulate the expression of the macrophage scavenger receptor A (SR-A) gene. We demonstrate that induction of the SR-A gene by M-CSF is dependent on AP-1 and cooperating Ets domain transcription factors that bind to sites in an M-CSF-dependent enhancer located 4.1 to 4.5 kb upstream of the transcriptional start site. In contrast, regulation by GM-CSF requires a separate enhancer located 4.5 to 4.8 kb upstream of the transcriptional start site that confers both immediate-early and sustained transcriptional responses. Results of a combination of DNA binding experiments and functional assays suggest that immediate transcriptional responses are mediated by DNA binding proteins that are constitutively bound to the GM-CSF enhancer and are activated by Ras. At 12 to 24 h after GM-CSF treatment, the GM-CSF enhancer becomes further occupied by additional DNA binding proteins that may contribute to sustained transcriptional responses. In concert, these studies indicate that GM-CSF and M-CSF differentially utilize Ras-dependent signal transduction pathways to regulate scavenger receptor gene expression, consistent with the distinct functional properties of M-CSF- and GM-CSF-derived macrophages.
Mots clés
Animals, Bacterial Proteins, genetics, Cell Differentiation, Cells, Cultured, DNA-Binding Proteins, metabolism, Enhancer Elements, Genetic, Gene Expression Regulation, Granulocyte-Macrophage Colony-Stimulating Factor, metabolism, Humans, Janus Kinase 2, Macrophage Colony-Stimulating Factor, metabolism, Macrophages, cytology, Membrane Transport Proteins, Mice, Mice, Transgenic, Milk Proteins, Oncogene Proteins, Protein-Tyrosine Kinases, metabolism, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-ets, Receptor, Macrophage Colony-Stimulating Factor, metabolism, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor, metabolism, STAT5 Transcription Factor, Signal Transduction, Trans-Activators, metabolism, Transcription Factor AP-1, metabolism, Transcription Factors, ras Proteins, metabolism
Référence
Mol Cell Biol. 1998 07;18(7):3851-61