SCF and C-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 cytokine s, Its synergy with granulocyte colony-stimulating factor (G-CSF) results i n important biologic and clinical effects, although the mechanism by which this occurs remains poorly understood. To investigate this interaction, thi s 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 re ceptor is functionally active, and the resultant MO7e-G cells recapitulate the proliferative synergy between SCF and G-CSF. When treated with both cyt okines, 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 p2 7(kip-1), I, addition, SCF and G-CSF induce the synergistic activation of c -fas, a proto-oncogene involved in propagation of mitogenic signals in hema topoietic cells. G-CSF, but not SCF, induces the tyrosine phosphorylation o f STAT1 and STATE, 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 comb ination 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 STAT 3 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 prov ide a powerful system in which the molecular basis of the synergy between S CF and G-CSF can be dissected. (C) 2000 by The American Society of Hematolo gy.