ROLE OF THE NUCLEAR-LOCALIZATION SEQUENCE IN FIBROBLAST GROWTH FACTOR-1-STIMULATED MITOGENIC PATHWAYS

Fibroblast growth factor-1 (FGF-1) is a potent mitogen for mesoderm- a nd neuroectoderm-derived cell types in vitro. However, a mutant FGF-1 with deletion in its nuclear localization sequence (NLS, residues 21-2 7) is not mitogenic in vitro. We demonstrated that synthetic peptides containing this NLS were able to stimulate DNA synthesis in a FGF rece ptor-independent manner after they were delivered into living NIH 3T3 cells by a cell-permeable peptide import technique. The stimulation of maximal DNA synthesis by these peptides required the presence of pept ides during the entire G(1) phase of the cell cycle. The mitogenic eff ect was specific for the NLS of FGF-1 because a peptide with double po int mutations at lysine residues was inactive in stimulating DNA synth esis. Our results suggest that the NLS plays an important role in the mitogenic pathway initiated by exogenous FGF-1 by its direct involveme nt in the nuclear transport and signaling of internalized FGF-1.