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J. Biol. Chem., Vol. 269, Issue 42, 26040-26044, 10, 1994
ME Venable, GC Blobe and LM Obeid
Normal cells become senescent in culture after a limited number of
population doublings becoming unable to respond to mitogens. This raises
the possibility of defects in mitogenic signaling pathways in cellular
senescence. In contrast to young human diploid fibroblasts (HDF), their
senescent counterparts failed to undergo protein kinase C translocation in
response to serum stimulation. On the other hand, phorbol 12-myristate
13-acetate was equally active in inducing protein kinase C translocation in
young and senescent HDF. This suggested a defect in generation of the
endogenous activator of protein kinase C, diacylglycerol. Stimulation of
young HDF with serum resulted in 3-4- fold generation of diacylglycerol
(DAG). In contrast, senescent cells displayed insignificant DAG formation
in response to serum. The mechanism of DAG generation was investigated
next. In young HDF, serum induced a 5-fold activation of the phospholipase
D (PLD) pathway as measured by the incorporation of exogenous ethanol into
phosphatidylethanol, which is a measure of the transphosphatidylation
reaction of PLD. In contrast, PLD in senescent cells was not activated by
serum. Since senescent cells demonstrate significant elevations in the
level of endogenous ceramide, the impact of ceramide on the PLD/DAG pathway
was also investigated. A soluble analog of ceramide, C6- ceramide, was
found to inhibit serum-stimulated DAG accumulation and PLD activation in
young cells. These data demonstrate for the first time a defect in PLD
activation in cellular senescence and suggest that ceramide may be
responsible for the inhibition of this pathway.
Identification of a defect in the phospholipase D/diacylglycerol pathway in cellular senescence
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710.
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