Synergism between stem cell factor and granulocyte-macrophage colony-stimulating factor on cell proliferation by induction of cyclins.
Synergism between stem cell factor (SCF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) has been shown to be essential for hematopoietic cell proliferation. Since HML-2 cells proliferate exponentially in the presence of SCF and GM-CSF together, we analyzed the molecular mechanism of the interaction between these two factors in the cells. An immediate-early gene product, c-myc, was additively upregulated in HML-2 cells by addition of a combination of SCF and GM-CSF. c-myc antisense oligonucleotides effectively suppressed cell proliferation and downregulated the induction of D3, E, A, and B cyclins in HML-2 cells stimulated with the two-factor combination. HML-2 cells arrested at the G0/G1 phase with SCF alone and expressed modest amounts of c-myc and cyclin D3, but not cyclin E. With GM-CSF treatment alone, the cells could not progress to the G2/M phase and expressed c-myc, cyclin D3 and cyclin E but not cyclins A or B. The addition of the counterpart cytokine resulted in cell cycle completion by induction of the deficient cyclins. Taken together, it appears that the induction of c-myc is an indispensable event in the proliferation of HML-2 cells and that the cytokines SCF and GM-CSF interact reciprocally for expression of all cyclins required for cell cycle progression.
Kamijo
Takehiko
T
Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan. tkamijo@hsp.md.shinshu-u.ac.jp
Koike
Kenichi
K
Nakazawa
Yozo
Y
Takeuchi
Koichi
K
Ishii
Eizaburo
E
Komiyama
Atsushi
A
D002453:Cell Cycle / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D016213:Cyclins / Q000096:biosynthesis*; D004357:Drug Synergism; D016193:G1 Phase / Q000502:physiology; D016195:G2 Phase / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis; D007947:Leukemia, Megakaryoblastic, Acute / Q000378:metabolism / Q000473:pathology; D008938:Mitosis / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D016196:S Phase / Q000502:physiology; D019089:Stem Cell Factor / Q000502:physiology*; D014407:Tumor Cells, Cultured
D016213:Cyclins; D017874:Immediate-Early Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D016271:Proto-Oncogene Proteins c-myc; D019089:Stem Cell Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor