FIBROBLAST VARIANTS NONRESPONSIVE TO FIBROBLAST GROWTH-FACTOR-1 ARE DEFECTIVE IN ITS NUCLEAR TRANSLOCATION

Fibroblast growth factors (FGF) elicit biological effects by binding t o high affinity cell-surface receptors and activation of receptor tyro sine kinase. We previously reported that two NIH/3T3 derivatives, NR31 and NR33 (NR cells), express high levels of full-length FGF-1 and exh ibit a complete spectrum of transformed phenotype, In the present stud y, we report that NR cells respond to the mitogenic stimulation of tru ncated FGF-1 but not to the full-length FGF-1. Incubation of the NR ce lls with either form of FGF-1 resulted in its binding to cell-surface FGF receptors, activation of mitogen-activated protein (MAP) kinase, a nd induction of c-fos and c-myc, These data demonstrate that the FGF r eceptor-mediated, MAP kinase-dependent signaling pathway is not defect ive in the NR cells. Our data further suggest that the activation of M AP kinase in response to full-length FGF-1 is not sufficient for mitog enesis. Subcellular distribution of exogenously added FGF-1 demonstrat ed that full-length FGF-1 fails to translocate to the nuclei of NR31 c ells, Although the full-length FGF-1 was detected in the nuclear fract ions of both NIH/3T3 and NR33 cells, its half-life is much shortened i n NR33 than in NIH/3T3 cells, These observations suggest that nonrespo nsiveness of the two NR cell lines may be due to defectiveness at diff erent steps of nuclear translocation mechanism of FGF-1.