Regulation of jun and fos gene expression in human monocytes by the macrophage colony-stimulating factor.
The macrophage colony-stimulating factor (M-CSF) is required for the growth and differentiation of mononuclear phagocytes. However, the signaling events responsible for these effects remain unclear. The present studies have examined the effects of M-CSF on potential signaling pathways involving expression of the jun and fos early response genes. Low levels of c-jun transcripts were detectable in resting human peripheral blood monocytes. Treatment of these cells with 10(3) units/ml human recombinant M-CSF was associated with rapid and transient increases in c-jun mRNA levels. Nuclear run-on assays and mRNA stability studies demonstrated that M-CSF regulates c-jun expression by both an increase in transcription rate and a prolongation in the half-life of c-jun transcripts. M-CSF treatment was also associated with a rapid induction of the jun-B gene, although expression of this gene was prolonged compared to that of c-jun. We further demonstrate that M-CSF increases c-fos mRNA levels in human monocytes through control at both the transcriptional and posttranscriptional levels. Maximal induction of the c-fos gene was followed by that for the fos-B gene. Moreover, M-CSF-induced expression of the fos-related gene, fra-1, was delayed compared to that for both c-fos and fos-B. Taken together, the results indicate that M-CSF treatment is associated with differential activation of multiple members of the jun/fos family and that expression of these genes could contribute to nuclear signaling mechanisms that regulate a specific program of monocyte differentiation.
Nakamura
T
T
Laboratory of Clinical Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115.
Datta
R
R
Kharbanda
S
S
Kufe
D
D
D002467:Cell Nucleus / Q000378:metabolism; D015342:DNA Probes / Q000302:isolation & purification; D004268:DNA-Binding Proteins / Q000097:blood / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D009000:Monocytes / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000097:blood / Q000235:genetics*; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D011519:Proto-Oncogenes / Q000235:genetics*; D012313:RNA / Q000302:isolation & purification; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D014157:Transcription Factors / Q000097:blood / Q000235:genetics*; D014158:Transcription, Genetic
D015342:DNA Probes; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D014157:Transcription Factors; D012313:RNA; D016173:Macrophage Colony-Stimulating Factor