Inhibition of colony-stimulating factor-1 promoter activity by the product of the Wilms' tumor locus.
Colony-stimulating factor-1 (CSF-1) is a member of the immediate early gene family, which is expressed in mitogen-stimulated quiescent fibroblasts. The biological effects of CSF-1 are multifaceted and include stimulation of the proliferation and differentiation of myeloid progenitors and activity of circulating monocytes and tissue-specific macrophages. Ablation of circulating levels of biologically active CSF-1 in mice leads to osteopetrosis and sterility, thus implicating a role for CSF-1 in bone remodeling and implantation. Identification of regulatory elements and cognate transcription factors that bind the csf-1 promoter and mediate such diverse expression patterns is of great interest. We identified a sequence element at -273 to -265 (relative to the transcription initiation site) in the murine csf-1 promoter, which contains overlapping consensus sequences for the Wilms' tumor protein (WT1), EGR-1, SP1, and SP3 proteins. WT1 and EGR-1 proteins produced in vitro bound to this sequence, and co-transfection of wt1 with a csf-1-cat reporter plasmid resulted in repression of promoter activity. Interestingly, nuclear extracts prepared from serum-stimulated C3H10T1/2 cells contained predominantly SP1 and SP3 binding activities, which recognized the -273 to -265 site. Thus repression of the csf-1 promoter by WT1 at this site may involve competition between SP1 family transcriptional activators and the WT1 repressor. Colony-stimulating factor-1 may be a physiologically relevant target gene for regulation by the WT1 transcription factor.
Harrington
M A
MA
Department of Medicine, Indiana University School of Medicine, Indianapolis 46202-5121.
Konicek
B
B
Song
A
A
Xia
X L
XL
Fredericks
W J
WJ
Rauscher
F J
FJ
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics*; D005347:Fibroblasts / Q000378:metabolism; D016162:Genes, Wilms Tumor; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics*; D051379:Mice; D008809:Mice, Inbred C3H; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D011401:Promoter Regions, Genetic; D016329:Sp1 Transcription Factor / Q000235:genetics; D051705:Sp3 Transcription Factor; D014157:Transcription Factors / Q000235:genetics; D014162:Transfection; D025721:WT1 Proteins; D016335:Zinc Fingers / Q000235:genetics
D004268:DNA-Binding Proteins; D009838:Oligodeoxyribonucleotides; D016329:Sp1 Transcription Factor; C497122:Sp3 protein, mouse; D014157:Transcription Factors; D025721:WT1 Proteins; D051705:Sp3 Transcription Factor; D016173:Macrophage Colony-Stimulating Factor