Regulation of FGF-3 gene expression in tumorigenic and non-tumorigenic clones of a human colon carcinoma cell line

The FGF-3 gene is constitutively expressed in tumorigenic clones from the S W613-S human colon carcinoma cell line but is silent in non-tumorigenic clo nes. We have investigated the transcriptional mechanisms responsible for th is differential expression. Mapping of DNase I-hypersensitive sites through out the FGF-3 gene and the region extending 15 kilobases upstream disclosed differences in the patterns obtained between tumorigenic and non-tumorigen ic cells. Transient expression assays carried out with a reporter gene driv en by FGF-3 promoter fragments of various lengths (0.143 to 11 kilobases) d id not reproduce the differential regulation of the resident gene between t he two cell types. The same constructs did exhibit a differential activity in stable transfectants, suggesting the involvement of a chromatin-based me chanism in this regulation. Under these conditions, even the 143-base pair minimal promoter fragment was able to drive the differential expression of the reporter gene. During the course of these analyses, several transcripti onal modulatory elements (mainly activators) were identified in the FGF-3 u pstream region and were found to colocalize with DNase I-hypersensitive sit es. Moreover, a putative new promoter was discovered 6 kilobases upstream o f FGF-8, Altogether, these data provide a basis for the elucidation of the complex regulation of the human FGF-3 gene.