INHIBITION OF COLONY-STIMULATING FACTOR-I 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 fibro blasts. The biological effects of CSF-1 are multifaceted and include s timulation of the proliferation and differentiation of myeloid progeni tors and activity of circulating monocytes and tissue-specific macroph ages. Ablation of circulating levels of biologically active CSF-1 in m ice leads to osteopetrosis and sterility, thus implicating a role for CSF-1 in bone remodeling and implantation. Identification of regulator y elements and cognate transcription factors that bind the csf-1 promo ter and mediate such diverse expression patterns is of great interest. We identified a sequence element at -273 to -265 (relative to the tra nscription initiation site) in the murine csf-1 promoter, which contai ns overlapping consensus sequences for the Wilms' tumor protein (WT1), EGR-1, SP1, and SP3 proteins. WT1 and EGR-1 proteins produced in vitr o bound to this sequence, and co-transfection of wt1 with a csf-1-cat reporter plasmid resulted in repression of promoter activity. Interest ingly, nuclear extracts prepared from serum-stimulated C3H10T1/2 cells contained predominantly SP1 and SP3 binding activities, which recogni zed the -273 to -265 site. Thus repression of the csf-1 promoter by WT 1 at this site may involve competition between SP1 family transcriptio nal activators and the WT1 repressor. Colony-stimulating factor-1 may be a physiologically relevant target gene for regulation by the WT1 tr anscription factor.