Sphingosine stimulates cellular proliferation via a protein kinase C-independent pathway.
Sphingosine stimulates cellular proliferation via a protein kinase C-independent pathway.
复制标题
DOI：
10.1016/s0021-9258(19)40197-x
复制
发表时间：
1990-01
期刊：
影响因子：
--
通讯作者：
Hong Zhang;N. E. Buckley;Karen Gibson;Sarah Spiegel
中科院分区：
文献类型：
--
作者：
Hong Zhang;N. E. Buckley;Karen Gibson;Sarah Spiegel
鞘氨醇是膜鞘脂的代谢产物，通常被认为对多种细胞类型具有细胞毒性。然而，我们发现低浓度的鞘氨醇会刺激 DNA 合成，并与已知的生长因子协同作用，诱导静止的 Swiss 3T3 成纤维细胞增殖。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胺，没有促有丝分裂作用，表明鞘氨醇不会诱导非特异性膜扰动。鞘氨醇被认为是蛋白激酶 C 的生理抑制剂，还可显着增强肿瘤促进剂 12-O-十四烷酰佛波醇-13-乙酸酯 (TPA) 的促有丝分裂作用。长期用佛波酯处理而导致蛋白激酶 C 缺乏的细胞中，鞘氨醇仍然会刺激 DNA 合成。在促有丝分裂浓度下，鞘氨醇不与蛋白激酶 C 结合，如它对佛波醇二丁酸酯结合缺乏影响所示。只有在细胞毒性范围内的较高浓度下，佛波醇二丁酸酯才会从其细胞结合位点发生位移。与鞘氨醇相反，H-7（一种已知的蛋白激酶 C 抑制剂）可抑制对 TPA 的有丝分裂反应以及 TPA 诱导的蛋白激酶 C 80 kDa 细胞底物的磷酸化。我们的结果表明，鞘氨醇可能作为细胞生长的正调节剂发挥着重要作用，其作用于根本不同的、不依赖于蛋白激酶 C 的途径。
Sphingosine, a metabolite of membrane sphingolipids, is generally considered to be cytotoxic for a variety of cell types. However, we have found that sphingosine at low concentrations stimulates DNA synthesis and acts synergistically with known growth factors to induce proliferation of quiescent Swiss 3T3 fibroblasts. Structurally related analogs of sphingosine, such as N-stearoylsphingosine and other long chain aliphatic amines, had no mitogenic effects, suggesting that sphingosine did not induce nonspecific membrane perturbations. Sphingosine, which has been proposed to be a physiological inhibitor of protein kinase C, also markedly potentiates the mitogenic effect of the tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA). Sphingosine still stimulates DNA synthesis in cells made protein kinase C deficient by prolonged treatment with phorbol ester. At mitogenic concentrations, sphingosine does not bind to protein kinase C as shown by its lack of effect on phorbol dibutyrate binding. Only at higher concentrations, in the cytotoxic range, was there a displacement of phorbol dibutyrate from its cellular-binding sites. In contrast to sphingosine, H-7, a known inhibitor of protein kinase C, inhibited the mitogenic response to TPA and the TPA-induced phosphorylation of the 80 kDa cellular substrate of protein kinase C. Our results suggest that sphingosine may play an important role as a positive regulator of cell growth acting in a fundamentally different, protein kinase C-independent pathway.