Many experiments investigating the transforming potential of FGF-1 and FGF-2 have been performed; however, a clear correlation between export of FGF-1 and FGF-2 and transformation was not apparent (2,9). For example, expression of the original FGF-2 coding sequence lacking a signal peptide in Balb/c 3T3 fibroblasts or BHK cells, resulted in transformation of the cells, and the detection of FGF-2 in the culture supernatant. However, transformation was not affected by neutralizing antibodies to FGF-2, indicating that the FGF-2 activation occurred within the cells (10). Forced secretion of FGF-2, by fusing a signal peptide onto the N-terminus of FGF-2, resulted in complete autocrine transformation of NIH 3T3 fibroblasts, as assessed by growth in soft agar, focus formation, and tumorigenicity and metastasis in athymic mice (9,11,12). Transformation could not be inhibited by neutralizing antibodies, but was reversed by suramin, a polyanionic drug known to inhibit growth factor-receptor interaction (9). S imilar results were obtained with FGF-1 (13). FGF-1, fused to a signal peptide, was readily secreted by the transfected NIH 3T3 cells, resulting in transformation of the cells, and the formation of highly vascularized tumors when injected into athymic mice. It appears that wild-type FGF-1 and FGF-2 by themselves transform cells only when expressed at high levels. In contrast, acquisition of a signal peptide converts FGF-1 and FGF-2 into highly transforming proteins analogous to other members of the FGF family. Consistent with these findings, the deletion of the signal sequence from FGF-4 significantly diminished its transforming activity (14).
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