Addition of growth hormone secretion signal to basic fibroblast growth factor results in cell transformation and secretion of aberrant forms of the protein.
Basic fibroblast growth factor (bFGF) is a potent mitogen for a wide variety of cell types. Unlike most growth factors, the primary translation product for bFGF appears to lack a secretory signal peptide. To explore the normal mode of bFGF release, as well as to investigate the growth factor's oncogenic potential, expression vectors were created for a bFGF cDNA and for a chimeric molecule in which the bFGF coding sequence was linked to the human growth hormone signal peptide sequence. Transfection of NIH3T3 cells with the bFGF cDNA vectors caused the synthesis of high levels of biologically active, cell-associated bFGF, but no evidence of transformation was detected. In contrast, the chimeric bFGF-signal peptide expression vector induced foci of transformation at a very high frequency. The transformed cells grew in soft agar and were tumorigenic in nude mice. The majority of the immunoreactive bFGF species made by the transformed cells was found in the conditioned medium and appeared to be posttranslationally modified, indicating that the chimeric bFGF-signal peptide molecule was processed through the secretory pathway. The secreted bFGF exhibited little mitogenic activity, suggesting that interaction of bFGF with its receptor likely occurs while the fusion protein is being processed along the secretory pathway.
Blam
S B
SB
Laboratory of Cellular and Molecular Biology, National Cancer Institute, Bethesda, Maryland 20892.
Mitchell
R
R
Tischer
E
E
Rubin
J S
JS
Silva
M
M
Silver
S
S
Fiddes
J C
JC
Abraham
J A
JA
Aaronson
S A
SA
D000818:Animals; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics; D005346:Fibroblast Growth Factors / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D006031:Glycosylation; D013006:Growth Hormone / Q000235:genetics*; D051379:Mice; D010641:Phenotype; D021382:Protein Sorting Signals / Q000235:genetics*; D014162:Transfection
D021382:Protein Sorting Signals; D005346:Fibroblast Growth Factors; D013006:Growth Hormone; D004247:DNA