A. Olivera et al., DIFFERENTIAL-EFFECTS OF SPHINGOMYELINASE AND CELL-PERMEABLE CERAMIDE ANALOGS ON PROLIFERATION OF SWISS 3T3 FIBROBLASTS, Biochimica et biophysica acta, L. Lipids and lipid metabolism, 1348(3), 1997, pp. 311-323
Metabolites of sphingomyelin, ceramide and sphingosine, have previousl
y been implicated in cell growth regulation. Here we show that cell-pe
rmeable ceramide analogs and treatment with sphingomyelinase, which hy
drolyzes sphingomyelin located on the outer leaflet of the bilayer, in
crease the progression of quiescent Swiss 3T3 fibroblasts through the
S phase of the cell cycle leading to an increase in cell division. Alt
hough both potentiate the mitogenic effects of several growth factors
[14], sphingomyelinase treatment antagonized the mitogenic effect pf t
he tumor promoter, 12-O-tetradecanoylphorbol 13-acetate (TPA), while c
eramide analogs had no effect, and sphingosine, a further metabolite o
f ceramide, potentiated the mitogenic effect of TPA. Concomitantly, sp
hingomyelinase, but not ceramide analogs, blunted the rapid increase i
n membrane-associated protein kinase C (PKC) activity induced by TPA w
ithout affecting the translocation of PKC alpha, delta, epsilon or zet
a isoforms. Moreover, in contrast to sphingosine which activates phosp
holipase D (PLD) leading to an increase in phosphatidic acid levels, s
phingomyelinase, but not ceramide analogs, reduced TPA-stimulated PLD
activity. Our results suggest that the signaling pathways utilized by
sphingomyelinase differ from those of cell-permeable ceramide analogs,
and both act differently than sphingosine. The differential effects o
f exogenous short-chain ceramide analogs and sphingomyelinase call for
caution in using these analogs as tools to study the role of ceramide
in diverse cellular functions. (C) 1997 Elsevier Science B.V.