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Blood, 15 November 2000, Vol. 96, No. 10, pp. 3422-3430
HEMATOPOIESIS
SCF and G-CSF lead to the synergistic induction of proliferation
and gene expression through complementary signaling pathways
Rafael F. Duarte and
David
A. Frank
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 G0/G1 phase of the
cell cycle occurs, associated with a suppression of the
cyclin-dependent kinase inhibitor p27kip-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.
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