The synergy between stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF): molecular basis and clinical relevance.
Stem cell factor (SCF), an essential growth factor in normal hematopoiesis, exerts potent effects when combined with cytokines. In particular, its synergy with granulocyte colony-stimulating factor (G-CSF) results in important biologic responses. These include enhancement of ex vivo long-term expansion of human primitive hematopoietic cells and increased mobilization of peripheral blood progenitor cells (PBPC) for transplantation. Despite the clinical importance of the interaction between SCF and G-CSF, the absence of a model system in which it could be studied at the cellular level had impaired the ability to understand the basis of their co-operation. To overcome this impediment, a system was recently generated which recapitulates the biologic synergy between SCF and G-CSF. MO7e-G cells have allowed the identification of key events in the synergistic actions of these cytokines on proliferation and gene expression. Among the biochemical and molecular events mediated by these cytokines are the down-regulation of p27kip1 and the independent phosphorylation of STAT3 on tyrosine and serine residues. Recent work has provided increasing evidence for the clinical importance of the combination of SCF and G-CSF. The elucidation of the intracellular events triggered by their receptors is now shedding light on key mediators of their synergistic effects. The identification of these pathways is of considerable importance for understanding fundamental aspects of hematopoiesis, and as potential targets for therapeutic intervention.
Duarte
Rafael F
RF
The Anthony Nolan Research Institute, The Royal Free Campus and UCL Medical School, London, United Kingdom.
Frank
David A
DA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics; D002455:Cell Division / Q000187:drug effects; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004268:DNA-Binding Proteins / Q000378:metabolism; D004357:Drug Synergism; D005786:Gene Expression Regulation / Q000187:drug effects; D016179:Granulocyte Colony-Stimulating Factor / Q000737:chemistry / Q000494:pharmacology*; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D019009:Proto-Oncogene Proteins c-kit / Q000187:drug effects / Q000502:physiology; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000187:drug effects / Q000502:physiology; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D019089:Stem Cell Factor / Q000737:chemistry / Q000494:pharmacology*; D015534:Trans-Activators / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D019089:Stem Cell Factor; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; D016179:Granulocyte Colony-Stimulating Factor; D050760:Cyclin-Dependent Kinase Inhibitor p27; D011494:Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D019009:Proto-Oncogene Proteins c-kit