title: 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.
abstract: Steel factor (SF) synergizes with a variety of hemopoietins to support the growth and differentiation of human progenitor cells. The human factor-dependent cell line MO7 has been used as a model to study the interaction of SF with other growth factors such as GM-CSF, because both factors support the proliferation of this cell line and are synergistic in combination. Previous studies have shown that this effect is not readily explained by the synergistic activation of early, cytosolic signal transduction intermediates such as tyrosine kinases, Raf-1, MAP2 kinase, or phospholipase C gamma. In an attempt to further explore the biological and biochemical mechanisms of the synergy between SF and GM-CSF, we examined the effects of these growth factors on the regulation 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 conditions. Only GM-CSF, but not SF, was able to stimulate G1-->S transition of MO7 cells after factor deprivation for 24 h. Northern blot analyses showed also differential effects of GM-CSF and SF on the expression 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 D2 mRNA, whereas both factors caused transient increases of c-fos and cyclin D3 mRNAs. When added simultaneously, GM-CSF and SF induced an at least additive increase of c-fos mRNA expression; this effect required 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 not 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-myc and cyclin D2 may explain why this cytokine does not support sustained 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 mechanism of synergy remains to be elucidated.
authors.affiliation: Dana-Faber Cancer Institute, Boston, Massachusetts.
authors.forename: M
authors.initials: M
authors.lastname: Hallek
authors.forename: K
authors.initials: K
authors.lastname: Ando
authors.forename: M
authors.initials: M
authors.lastname: Eder
authors.forename: K
authors.initials: K
authors.lastname: Slattery
authors.forename: F
authors.initials: F
authors.lastname: Ajchenbaum-Cymbalista
authors.forename: J D
authors.initials: JD
authors.lastname: Griffin
mesh_terms: D002455:Cell Division; D016213:Cyclins / Q000235:genetics*; D004357:Drug Synergism; D016193:G1 Phase; D015973:Gene Expression Regulation, Leukemic; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D016298:Hematopoietic Cell Growth Factors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007947:Leukemia, Megakaryoblastic, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011519:Proto-Oncogenes / Q000235:genetics; D016196:S Phase; D015398:Signal Transduction; D019089:Stem Cell Factor; D014157:Transcription Factors / Q000235:genetics*; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000473:pathology
chemical_list: D016213:Cyclins; D016298:Hematopoietic Cell Growth Factors; D019089:Stem Cell Factor; D014157:Transcription Factors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor