Increases in phosphatidic acid levels accompany sphingosine-stimulated proliferation of quiescent Swiss 3T3 cells.
Increases in phosphatidic acid levels accompany sphingosine-stimulated proliferation of quiescent Swiss 3T3 cells.
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DOI：
10.1016/s0021-9258(17)45361-0
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发表时间：
1990-12
期刊：
影响因子：
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通讯作者：
Hong Zhang;N. N. Desai-N.;J. M. Murphey;Sarah Spiegel
中科院分区：
文献类型：
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作者：
Hong Zhang;N. N. Desai-N.;J. M. Murphey;Sarah Spiegel
鞘氨醇是细胞鞘脂的分解产物，最近已显示刺激DNA合成并与已知生长因子协同作用以诱导静止的Swiss 3 T3成纤维细胞的增殖（Hong，Z.，Buckley，N. E、吉布森，K.，和Spiegel，S.（1990）J.Biol.Chem.265，76-81）。本研究表明，促有丝分裂浓度的鞘氨醇诱导早期增加胞浆磷脂酸，这是一个有效的促有丝分裂瑞士3 T3细胞。结构相关的鞘氨醇类似物，例如N-硬脂酰鞘氨醇和其他长链脂肪族胺，不能模拟鞘氨醇的促有丝分裂作用，也不能提高磷脂酸水平。鞘氨醇不仅刺激[3 H]胸苷掺入与磷脂酸相似的效率和动力学，它也诱导类似的形态学改变。鞘氨醇和磷脂酸与多种生长因子如胰岛素、表皮生长因子、成纤维细胞生长因子和12-O-十四酰佛波醇13-乙酸酯协同作用。与此形成鲜明对比的是，鞘氨醇和磷脂酸在其他生长因子存在或不存在的情况下没有相加或协同作用。鞘氨醇和磷脂酸都刺激DNA合成的细胞中蛋白激酶C缺陷的长期治疗与佛波酯和鞘氨醇仍然刺激类似的增加磷脂酸在这些细胞中。此外，类似于磷脂酸对Swiss 3 T3细胞中信号转导的作用，促有丝分裂浓度的鞘氨醇也抑制cAMP积累并触发聚磷酸肌醇的水解。我们的研究结果表明，鞘氨醇和磷脂酸控制瑞士3 T3细胞的细胞反应，通过一个共同的途径。鉴于磷脂酸在信号转导和细胞增殖中的突出作用，我们观察到鞘氨醇在促有丝分裂浓度下增加磷脂酸的水平，并模拟磷脂酸对信号转导的影响，这对鞘氨醇的作用机制具有重要意义。
Sphingosine, a breakdown product of cellular sphingolipids, has recently been shown to stimulate DNA synthesis and act synergistically with known growth factors to induce proliferation of quiescent Swiss 3T3 fibroblasts (Hong, Z., Buckley, N. E., Gibson, K., and Spiegel, S. (1990) J. Biol. Chem. 265, 76-81). The present study demonstrates that mitogenic concentrations of sphingosine induce early increases in cytosolic phosphatidic acid, which is a potent mitogen for Swiss 3T3 cells. Structurally related analogs of sphingosine, such as N-stearoylsphingosine and other long chain aliphatic amines, did not mimic the mitogenic effect of sphingosine and did not elevate phosphatidic acid levels. Sphingosine not only stimulated [3H]thymidine incorporation with similar efficiency and kinetics as phosphatidic acid, it also induced similar morphological alterations. Both sphingosine and phosphatidic acid acted synergistically with a variety of growth factors, such as, insulin, epidermal growth factor, fibroblast growth factor, and 12-O-tetradecanoylphorbol 13-acetate. In sharp contrast, sphingosine and phosphatidic acid did not have additive or synergistic effects in either the presence or absence of other growth factors. Both sphingosine and phosphatidic acid stimulated DNA synthesis in cells made protein kinase C-deficient by prolonged treatment with phorbol ester and sphingosine still stimulated similar increases in phosphtidic acid in these cells. Furthermore, similar to the actions of phosphatidic acid on signal transduction in Swiss 3T3 cells, mitogenic concentrations of sphingosine also inhibit cAMP accumulation and trigger the hydrolysis of polyphosphoinositides. Our findings indicate that sphingosine and phosphatidic acid control cellular responses in Swiss 3T3 cells through a common pathway. In view of the prominent role of phosphatidic acid in signal transduction and cellular proliferation, our observations that sphingosine, at mitogenic concentrations, increases the level of phosphatidic acid and also mimics the effects of phosphatidic acid on signal transduction, have important implications for the mechanism of action of sphingosine.