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 overexpression of HMW FGF-2 forms in fibroblasts promotes growth in low serum, whereas overexpression of LMW FGF-2 does not. The HMW FGF-2 forms have two functional domains: an amino-terminal extension and a common 18-kDa amino acid sequence. To investigate the role of these regions in the intracrine signaling of HMW FGF-2, we produced stable transfectants of NIH 3T3 fibroblasts 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/nucleolus and induce growth in low serum. The nuclear forms of FGF-2 trigger a mitogenic stimulus under serum starvation conditions and do not specifically 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 pathways.
Arese
M
M
Department of Cell Biology, New York University Medical Center, New York, New York 10016, USA. aresem01@mcrcr.med.nyu.edu
Chen
Y
Y
Florkiewicz
R Z
RZ
Gualandris
A
A
Shen
B
B
Rifkin
D B
DB
D016475:3T3 Cells / Q000187:drug effects / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D001973:Bromodeoxyuridine / Q000378:metabolism; D002455:Cell Division / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism*; D003001:Cloning, Molecular; D003114:Colony-Forming Units Assay; D004247:DNA / Q000096:biosynthesis; D016222:Fibroblast Growth Factor 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D008970:Molecular Weight; D010641:Phenotype; D020033:Protein Isoforms; D015398:Signal Transduction
D020033:Protein Isoforms; D016222:Fibroblast Growth Factor 2; D004247:DNA; D001973:Bromodeoxyuridine