Involvement of immediate-early gene expression in the synergistic effects of steel factor in combination with granulocyte-macrophage colony-stimulating factor or interleukin-3 on proliferation of a human factor-dependent cell line.
Steel factor (SLF) synergizes with granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3) to stimulate proliferation of human factor-dependent cell line, MO7e. To elucidate molecular mechanisms underlying this synergism, induction of immediate-early genes was studied. Treatment of MO7e cells with SLF, GM-CSF, and IL-3 induced/enhanced expression of c-fos, junB, egr-1, and c-myc genes. SLF treatment of MO7e cells led to higher expression of c-fos, junB, and egr-1 genes than did treatment with GM-CSF or IL-3. However, GM-CSF and IL-3 had more prolonged effects on enhancement of the c-myc gene than SLF. Using optimal dosages for cell proliferation, induction of c-fos and junB was greater than additive with SLF plus GM-CSF or IL-3, as compared with each factor alone. Using suboptimal amounts of SLF with optimal GM-CSF or IL-3, induction of c-fos, junB, egr-1, and c-myc genes was greater than additive. De novo protein synthesis was not required for greater induction of these immediate-early genes by the combination of SLF plus GM-CSF. Based on nuclear run-on and actinomycin D experiments, the data suggest that the synergistic effects of SLF plus GM-CSF on the induction of immediate-early genes may be mediated in part at the level of transcription and mRNA stabilization for c-fos, at the level of mRNA stabilization for junB, and at the level of transcription for egr-1.
Horie
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Department of Medicine (Hematology/Oncology), Indiana University School of Medicine, Indianapolis 46202-5121.
Broxmeyer
H E
HE
D002455:Cell Division / Q000187:drug effects; D015342:DNA Probes; D004268:DNA-Binding Proteins / Q000235:genetics*; D051766:Early Growth Response Protein 1; D015870:Gene Expression / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D016762:Genes, fos / Q000187:drug effects*; D016758:Genes, jun / Q000187:drug effects*; D016259:Genes, myc / Q000235:genetics*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D016298:Hematopoietic Cell Growth Factors / Q000494:pharmacology*; D006801:Humans; D017874:Immediate-Early Proteins; D007377:Interleukin-3 / Q000494:pharmacology*; D007700:Kinetics; D007947:Leukemia, Megakaryoblastic, Acute; D012333:RNA, Messenger / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000494:pharmacology; D015183:Restriction Mapping; D019089:Stem Cell Factor; D014157:Transcription Factors / Q000235:genetics*; D014407:Tumor Cells, Cultured; D016335:Zinc Fingers / Q000235:genetics
D015342:DNA Probes; D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D016298:Hematopoietic Cell Growth Factors; D017874:Immediate-Early Proteins; D007377:Interleukin-3; D012333:RNA, Messenger; D011994:Recombinant Proteins; D019089:Stem Cell Factor; D014157:Transcription Factors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor