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 SW613-S human colon carcinoma cell line but is silent in non-tumorigenic clones. We have investigated the transcriptional mechanisms responsible for this differential expression. Mapping of DNase I-hypersensitive sites throughout the FGF-3 gene and the region extending 15 kilobases upstream disclosed differences in the patterns obtained between tumorigenic and non-tumorigenic cells. Transient expression assays carried out with a reporter gene driven by FGF-3 promoter fragments of various lengths (0.143 to 11 kilobases) did not reproduce the differential regulation of the resident gene between the two cell types. The same constructs did exhibit a differential activity in stable transfectants, suggesting the involvement of a chromatin-based mechanism 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 transcriptional modulatory elements (mainly activators) were identified in the FGF-3 upstream region and were found to colocalize with DNase I-hypersensitive sites. Moreover, a putative new promoter was discovered 6 kilobases upstream of FGF-3. Altogether, these data provide a basis for the elucidation of the complex regulation of the human FGF-3 gene.