Inhibition of colony-stimulating factor-1 promoter activity by the product of the Wilms' tumor locus

• Published in: The Journal of biological chemistry 1993-10, Vol.268 (28), p.21271-21275
• Main Authors: M A Harrington, B Konicek, A Song, X L Xia, W J Fredericks, F J Rauscher, 3rd
• Format: Article
• Language: English
• Subjects: Animals; Base Sequence; Biological and medical sciences; Cell Line; DNA-Binding Proteins - genetics; Fibroblasts - metabolism; Fundamental and applied biological sciences. Psychology; Genes, Wilms Tumor; Macrophage Colony-Stimulating Factor - genetics; Mice; Mice, Inbred C3H; Molecular and cellular biology; Molecular genetics; Molecular Sequence Data; Oligodeoxyribonucleotides; Promoter Regions, Genetic; Sp1 Transcription Factor - genetics; Sp3 Transcription Factor; Transcription Factors - genetics; Transcription. Transcription factor. Splicing. Rna processing; Transfection; WT1 Proteins; Zinc Fingers - genetics
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/s0021-9258(19)36920-0

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.