SCF and G-CSF lead to the synergistic induction of proliferation and gene expression through complementary signaling pathways.
Stem cell factor (SCF) is a potent costimulatory molecule for many cytokines. Its synergy with granulocyte colony-stimulating factor (G-CSF) results in important biologic and clinical effects, although the mechanism by which this occurs remains poorly understood. To investigate this interaction, this study used a retroviral vector to transduce the G-CSF receptor into MO7e cells, which are known to express the SCF receptor. The transduced G-CSF receptor is functionally active, and the resultant MO7e-G cells recapitulate the proliferative synergy between SCF and G-CSF. When treated with both cytokines, a marked shortening of the G(0)/G(1) phase of the cell cycle occurs, associated with a suppression of the cyclin-dependent kinase inhibitor p27(kip-1). In addition, SCF and G-CSF induce the synergistic activation of c-fos, a proto-oncogene involved in propagation of mitogenic signals in hematopoietic cells. G-CSF, but not SCF, induces the tyrosine phosphorylation of STAT1 and STAT3, transcription factors that can mediate the induction of c-fos. However, SCF induces phosphorylation of STAT3 on serine727 (ser727), which is necessary for maximal STAT transcriptional activity, and the combination of SCF and G-CSF leads to complete STAT3 phosphorylation on ser727. The pathways by which SCF and G-CSF lead to serine phosphorylation of STAT3 are distinct and are partially dependent on phosphatidylinositol-3 kinase and ERKs, pathways that are also necessary for the synergistic effects of SCF and G-CSF on proliferation and c-fos induction. Thus, MO7e-G cells provide a powerful system in which the molecular basis of the synergy between SCF and G-CSF can be dissected.
Duarte
R F
RF
Department of Adult Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Boston, MA, USA.
Frank
D A
DA
D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology* / Q000502:physiology; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D000090063:Proto-Oncogene Mas; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects / Q000378:metabolism; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000494:pharmacology* / Q000502:physiology; D015534:Trans-Activators / Q000187:drug effects / Q000378:metabolism; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D016179:Granulocyte Colony-Stimulating Factor; D008869:Microtubule-Associated Proteins; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D000090063:Proto-Oncogene Mas; D016760:Proto-Oncogene Proteins c-fos; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D012694:Serine; D019089:Stem Cell Factor; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; C000715470:MAS1 protein, human; C494079:STAT1 protein, human; C494086:STAT3 protein, human