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J. Biol. Chem., Vol. 265, Issue 1, 76-81, Jan, 1990
H Zhang, NE Buckley, K Gibson and S Spiegel
Sphingosine, a metabolite of membrane sphingolipids, is generally
considered to be cytotoxic for a variety of cell types. However, we have
found that sphingosine at low concentrations stimulates DNA synthesis and
acts synergistically with known growth factors to induce proliferation of
quiescent Swiss 3T3 fibroblasts. Structurally related analogs of
sphingosine, such as N-stearoylsphingosine and other long chain aliphatic
amines, had no mitogenic effects, suggesting that sphingosine did not
induce nonspecific membrane perturbations. Sphingosine, which has been
proposed to be a physiological inhibitor of protein kinase C, also markedly
potentiates the mitogenic effect of the tumor promoter,
12-O-tetradecanoylphorbol-13-acetate (TPA). Sphingosine still stimulates
DNA synthesis in cells made protein kinase C deficient by prolonged
treatment with phorbol ester. At mitogenic concentrations, sphingosine does
not bind to protein kinase C as shown by its lack of effect on phorbol
dibutyrate binding. Only at higher concentrations, in the cytotoxic range,
was there a displacement of phorbol dibutyrate from its cellular-binding
sites. In contrast to sphingosine, H-7, a known inhibitor of protein kinase
C, inhibited the mitogenic response to TPA and the TPA-induced
phosphorylation of the 80 kDa cellular substrate of protein kinase C. Our
results suggest that sphingosine may play an important role as a positive
regulator of cell growth acting in a fundamentally different, protein
kinase C-independent pathway.
Sphingosine stimulates cellular proliferation via a protein kinase C- independent pathway
Department of Biochemistry and Molecular Biology, Georgetown University Medical Center, Washington, D.C. 20007.
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