SIGNAL-TRANSDUCTION OF STEEL FACTOR AND GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR - DIFFERENTIAL REGULATION OF TRANSCRIPTION FACTOR AND G1 CYCLIN GENE-EXPRESSION, AND OF PROLIFERATION IN THE HUMAN FACTOR-DEPENDENT CELL-LINE MO7

Steel factor (SF) synergizes with a variety of hemopoietins to support the growth and differentiation of human progenitor cells. The human f actor-dependent cell line MO7 has been used as a model to study the in teraction of SF with other growth factors such as GM-CSF, because both factors support the proliferation of this cell line and are synergist ic in combination. Previous studies have shown that this effect is not readily explained by the synergistic activation of early, cytosolic s ignal transduction intermediates such as tyrosine kinases, Raf-1, MAP2 kinase, or phospholipase C gamma. In an attempt to further explore th e biological and biochemical mechanisms of the synergy between SF and GM-CSF, we examined the effects of these growth factors on the regulat ion of nuclear proto-oncogenes, cell cycle control genes, and G1 --> S transition of MO7 cells. Individually, GM-CSF was a much more potent growth factor for MO7 cells than SF, particularly under serum-free con ditions. Only GM-CSF, but not SF, was able to stimulate G1 --> S trans ition of MO7 cells after factor deprivation for 24 h. Northern blot an alyses showed also differential effects of GM-CSF and SF on the expres sion of some nuclear proto-oncogenes and G1 cyclins. GM-CSF (10 ng/ml) , but not SF (20 ng/ml) increased the expression of c-myc and cyclin D 2 mRNA, whereas both factors caused transient increases of c-fos and c yclin D3 mRNAs. When added simultaneously, GM-CSF and SF induced an at least additive increase of c-fos mRNA expression; this effect require d the presence of fetal calf serum. No additive effects of GM-CSF and SF on c-myc, cyclin D2 or D3 mRNA expression were observed. C-jun and c-myb mRNAs were constitutively expressed in the MO7 cell line, but no t further increased after stimulation with GM-CSF or SF for 15 min to 48 h. The inability of SF to induce growth promoting genes such as c-m yc and cyclin D2 may explain why this cytokine does not support sustai ned proliferation of MO7 cells. These observations suggest that SF and GM-CSF exert different effects on the expression of genes involved in regulatory pathways of cell proliferation, but the molecular mechanis m of synergy remains to be elucidated.