Sphingosine and sphingosine 1-phosphate in cellular proliferation: relationship with protein kinase C and phosphatidic acid.

Journal of lipid mediators Pub Date : 1993-11-01
S Spiegel
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Abstract

Previous studies from our laboratory have shown that sphingosine (Zhang et al. (1990) J. Biol. Chem. 265, 76-81) and sphingosine 1-phosphate (Zhang et al. (1991) J. Cell. Biol. 114, 155-167), metabolites of membrane sphingolipids, stimulate release of calcium from internal sources and increase proliferation of quiescent Swiss 3T3 fibroblasts acting in a fundamentally different, protein kinase C-independent pathway. The mitogenic effect of sphingosine was accompanied by an increase in the levels of phosphatidic acid (PA), a potent mitogen for a variety of cell types, that may function as an intracellular second messenger (Zhang et al. (1990) J. Biol. Chem. 265, 21309-21316). Sphingosine also induced early increases in sphingosine 1-phosphate (SPP) levels that preceded the increase in PA (Desai et al. (1992) J. Biol. Chem. 267, 23122-23128). SPP itself produced a more rapid increase in PA, thus suggesting that it may mediate the effects of sphingosine on PA accumulation. The concentration dependence for the formation of PA induced by SPP correlated with its effect on DNA synthesis. Similar to sphingosine, SPP also stimulated the activity of phospholipase D, although a significant effect was observed at a much lower concentration. However, in contrast to previous reports with sphingosine, SPP did not inhibit the PA phosphohydrolase activity in cell homogenates. Thus, in addition to its effect on mobilization of calcium, SPP can increase the level of PA, most likely via activation of phospholipase D. We suggest that SPP mediates the effect of sphingosine on PA accumulation in Swiss 3T3 fibroblasts and may regulate cellular proliferation by affecting multiple transmembrane signaling pathways.

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鞘氨醇和鞘氨醇1-磷酸在细胞增殖中的作用:与蛋白激酶C和磷脂酸的关系。
我们实验室以前的研究表明,鞘氨醇(Zhang et al.(1990)。化学,265,76-81)和1-磷酸鞘氨醇(Zhang et . (1991) J. Cell。细胞膜鞘脂的代谢物,刺激钙从内部来源释放,并增加静止的瑞士3T3成纤维细胞的增殖,作用于一个完全不同的,不依赖蛋白激酶c的途径。鞘氨醇的有丝分裂作用伴随着磷脂酸(PA)水平的增加,磷脂酸是多种细胞类型的一种有效的有丝分裂原,可能作为细胞内第二信使起作用(Zhang et al. (1990) J. Biol。化学,265,21309 -21316)。鞘氨醇还能诱导鞘氨醇1-磷酸(SPP)水平在PA升高之前早期升高(Desai et al. (1992) J. Biol。化学,267,23122-23128)。SPP本身产生的PA增加速度更快,这表明SPP可能介导鞘氨醇对PA积累的影响。SPP诱导PA形成的浓度依赖性与其对DNA合成的影响有关。与鞘氨醇类似,SPP也能刺激磷脂酶D的活性,尽管在较低的浓度下观察到显著的影响。然而,与先前关于鞘氨醇的报道相反,SPP并没有抑制细胞匀浆中PA磷酸水解酶的活性。因此,SPP除了对钙的动员作用外,还可以通过激活磷脂酶d来增加PA的水平。我们认为SPP介导鞘氨醇对Swiss 3T3成纤维细胞中PA积累的影响,并可能通过影响多种跨膜信号通路来调节细胞增殖。
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Differential sensitivity of mouse strains to platelet activating factor-induced vasopermeability and mortality: effect of antagonists. 5-Lipoxygenase activity in the human pancreas. PAF-releasing factor in human serum and inflammatory exudate. Secretory non-pancreatic group II phospholipase A2: role in physiologic and inflammatory processes. Sphingosine and sphingosine 1-phosphate in cellular proliferation: relationship with protein kinase C and phosphatidic acid.
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