INTERACTION OF CERAMIDES, SPHINGOSINE, AND SPHINGOSINE 1-PHOSPHATE IN REGULATING DNA-SYNTHESIS AND PHOSPHOLIPASE-D ACTIVITY

被引:146
作者
GOMEZMUNOZ, A
WAGGONER, DW
OBRIEN, L
BRINDLEY, DN
机构
[1] UNIV ALBERTA,DEPT BIOCHEM,SIGNAL TRANSDUCT LABS,EDMONTON,AB T6G 2S2,CANADA
[2] UNIV ALBERTA,LIPID & LIPOPROT RES GRP,EDMONTON,AB T6G 2S2,CANADA
关键词
D O I
10.1074/jbc.270.44.26318
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
C-2- and C-6-ceramides (N-acetylsphingosine and N-hexanoylsphingosine, respectively) abolished the stimulation of DNA synthesis by sphingosine 1-phosphate in rat fibroblasts. This inhibition by ceramide was partially prevented by insulin C-2-ceramide did not alter the stimulation of DNA synthesis by insulin and decreased the sphingosine-induced stimulation by only 16%. The ceramides did not significantly modify the actions of sphingosine or sphingosine l-phosphate in decreasing cAMP concentrations. C-2- and C-6-ceramides blocked the activation of phospholipase D by sphingosine l-phosphate, and this inhibition was not affected by insulin. Okadaic acid decreased the activation of phospholipase D by sphingosine l-phosphate and did not reverse the inhibitory effect of C-2-ceramide on this activation. Therefore, this effect of C-2-ceramide is unlikely to involve the stimulation of phosphoprotein phosphatase activity. Sphingosine did not activate phospholipase D activity significantly after 10 min. C-2-ceramide stimulated the conversion of exogenous [H-3]sphingosine 1-phosphate to sphingosine and ceramide in fibroblasts. Ceramides can inhibit some effects of sphingosine l-phosphate by stimulating its degradation via a phosphohydrolase that also hydrolyzes phosphatidate. Furthermore, C-2- and C-6-ceramides stimulated ceramide production from endogenous lipids, and this could propagate the intracellular signal. This work demonstrates that controlling the production of ceramide versus sphingosine and sphingosine l-phosphate after sphingomyelinase activation could have profound effects on signal transduction.
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收藏
页码:26318 / 26325
页数:8
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