Oncogenic Ras-induced proliferation requires autocrine fibroblast growth factor 2 signaling in skeletal muscle cells.
Constitutively activated Ras proteins are associated with a large number of human cancers, including those originating from skeletal muscle tissue. In this study, we show that ectopic expression of oncogenic Ras stimulates proliferation of the MM14 skeletal muscle satellite cell line in the absence of exogenously added fibroblast growth factors (FGFs). MM14 cells express FGF-1, -2, -6, and -7 and produce FGF protein, yet they are dependent on exogenously supplied FGFs to both maintain proliferation and repress terminal differentiation. Thus, the FGFs produced by these cells are either inaccessible or inactive, since the endogenous FGFs elicit no detectable biological response. Oncogenic Ras-induced proliferation is abolished by addition of an anti-FGF-2 blocking antibody, suramin, or treatment with either sodium chlorate or heparitinase, demonstrating an autocrine requirement for FGF-2. Oncogenic Ras does not appear to alter cellular export rates of FGF-2, which does not possess an NH(2)-terminal or internal signal peptide. However, oncogenic Ras does appear to be involved in releasing or activating inactive, extracellularly sequestered FGF-2. Surprisingly, inhibiting the autocrine FGF-2 required for proliferation has no effect on oncogenic Ras-mediated repression of muscle-specific gene expression. We conclude that oncogenic Ras-induced proliferation of skeletal muscle cells is mediated via a unique and novel mechanism that is distinct from Ras-induced repression of terminal differentiation and involves activation of extracellularly localized, inactive FGF-2.
The Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Colorado 80309, USA.
Y V
YV
Fedorov
R S
RS
Rosenthal
B B
BB
Olwin
D000818:Animals; D019898:Autocrine Communication / Q000502:physiology; D002455:Cell Division / Q000502:physiology*; D002460:Cell Line; D005343:Fibrinolytic Agents / Q000494:pharmacology; D005346:Fibroblast Growth Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017930:Genes, Reporter; D019812:Heparan Sulfate Proteoglycans / Q000494:pharmacology; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D051379:Mice; D018482:Muscle, Skeletal / Q000166:cytology* / Q000187:drug effects; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013498:Suramin / Q000494:pharmacology; D014162:Transfection; D018631:ras Proteins / Q000378:metabolism*
D005343:Fibrinolytic Agents; D019812:Heparan Sulfate Proteoglycans; D011994:Recombinant Proteins; D013498:Suramin; D005346:Fibroblast Growth Factors; D006493:Heparin; D018631:ras Proteins