Nucleolar association of fibroblast growth factor 3 via specific sequence motifs has inhibitory effects on cell growth.
The dual subcellular fate of fibroblast growth factor 3 (FGF3) is determined by the competing effects of amino-terminal signals for nuclear localization and secretion (P. Kiefer, P. Acland, D. Pappin, G. Peters, and C. Dickson, EMBO J. 13:4126-4136, 1994). Mutation analysis has implicated additional basic domains in the carboxy-terminal region of the protein as necessary for nuclear uptake and the association of FGF3 with the nucleoli. Immunogold electron microscopy shows that FGF3 is predominantly within the dense fibrillar component of the nucleolus. A form of FGF3 that localizes exclusively in the nucleus and nucleolus was generated by removing signals for secretion, and expression of this nonsecreted FGF3 in a mammary epithelial cell line resulted in slowly growing colonies of enlarged cells. Thus, nuclear import and nucleolar association of FGF3 are determined by the concerted interaction of several distinct motifs, and the exclusive production of the nuclear isoform can inhibit DNA synthesis and cell proliferation.
Kiefer
P
P
Imperial Cancer Research Fund, London, United Kingdom.
Dickson
C
C
D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport; D002451:Cell Compartmentation; D002455:Cell Division / Q000187:drug effects; D002466:Cell Nucleolus / Q000378:metabolism* / Q000648:ultrastructure; D002478:Cells, Cultured; D002999:Clone Cells; D004247:DNA / Q000096:biosynthesis; D004252:DNA Mutational Analysis; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D006131:Growth Inhibitors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D016253:Microscopy, Immunoelectron; D008969:Molecular Sequence Data; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D014162:Transfection
D006131:Growth Inhibitors; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D005346:Fibroblast Growth Factors; D004247:DNA