REGULATION OF THE C-FMS PROMOTER IN MURINE TUMOR-CELL LINES

Macrophage colony-stimulating factor (CSF-1) mRNA was detected in a wi de range of murine tumour cell lines. Stable transfection with a CSF-1 receptor (c-fms) expression plasmid increased the number and size of colonies formed in soft agar by tumour cell lines that were already cl onogenic, but did not induce transformation in non-clonogenic lines. T o identify mechanisms that might lead to ectopic expression of c-fms, the regulation of the exon 2 promoter of the gene, which flanks the tr anscription start sites in macrophages, was examined. In transient and stable transfections this promoter was as active in non-macrophage tu mour cell lines as it was in RAW264 macrophages. Promoter activity in non-macrophage lines was serum-dependent and was activated further in lines stably transfected with c-fms. Cis-acting elements required for serum-dependent activity lay outside the 300 bp proximal promoter that was sufficient for maximal activity in RAW264 macrophages, but the c- fms-responsive elements were retained in the proximal promoter. Exon 2 promoter activity was selectively suppressed in non-macrophage fines inclusion of intron 2, which has been implicated transcription attenua tion. Lewis lung carcinoma cells were able to partly bypass this block and expressed c-fms mRNA when grown in limiting serum. The finding th at c-fms promoter activity and c-fms mRNA levels are responsive to gro wth factor signalling pathways provides an insight into mechanisms tha t may lead to ectopic c-fms expression in tumour cells.