Nuclear activities of basic fibroblast growth factor: Potentiation of low-serum growth mediated by natural or chimeric nuclear localization signals

Human basic fibroblast growth factor (FGF-2) occurs in four isoforms: a low molecular weight (LMW FGF-2, 18 kDa) and three high molecular weight (HMW FGF-2, 22, 22.5, and 24 kDa) forms. LMW FGF-2 is primarily cytoplasmic and functions in an autocrine manner, whereas HMW FGF-2s are nuclear and exert activities through an intracrine, perhaps nuclear, pathway. Selective overe xpression of HMW FGF-2 forms in fibroblasts promotes growth in low serum, w hereas overexpression of LMW FGF-2 does not. The HMW FGF-2 forms have two f unctional domains: an amino-terminal extension and a common 18-kDa amino ac id sequence. To investigate the role of these regions in the intracrine sig naling of HMW FGF-2, we produced stable transfectants of NIH 3T3 fibroblast s overexpressing either individual HMW FGF-2 forms or artificially nuclear- targeted LMW FGF-2. All of these forms of FGF-2 localize to the nucleus/nuc leolus and induce growth in low serum. The nuclear forms of FGF-2 trigger a mitogenic stimulus under serum starvation conditions and do not specifical ly protect the cells from apoptosis. These data indicate the existence of a specific role for nuclear FGF-2 and suggest that LMW FGF-2 represents the biological messenger in both the autocrine/paracrine and intracrine FGF-2 p athways.