The formation of ceramide from sphingomyelin is associated with cellular apoptosis
The formation of ceramide from sphingomyelin is associated with cellular apoptosis
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DOI：
10.18388/abp.1998_4225
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发表时间：
1998-01-01
影响因子：
1.7
通讯作者：
Dawson, S
中科院分区：
文献类型：
--
作者：
Dawson, G;Goswami, R;Dawson, S
未成熟的E-细胞的表面IgM受体的交联的凋亡反应提供了一个很好的模型，细胞死亡，我们显示在WEHI-231 B-细胞，细胞凋亡的时间过程对应于神经酰胺的形成增加，测量质量（使用二酰基甘油激酶法）或放射性标记的[H-3]棕榈酸酯。鞘氨醇生物合成的抑制剂对WEHI-231中抗IgM诱导的细胞死亡没有影响，但神经酰胺酶的抑制剂加速细胞凋亡，这表明鞘磷脂酶的激活是细胞凋亡的关键事件。我们已经证明了这一点，在体外测定中性鞘磷脂酶。细胞凋亡在正常脑发育中也是重要的，神经元存活依赖于生长因子（胰岛素、神经生长因子等）对磷脂酰肌醇3-激酶（PI 3-激酶）的激活。撤除这些生长因子或用渥曼青霉素或LY 294002抑制PI 3-激酶激活促凋亡CPP 32（Yama/Apopain/半胱天冬酶3，EC 3.4.22），激活中性鞘磷脂酶并增加永生化背根神经节细胞系F-II中的神经酰胺形成。抗细胞凋亡的保护作用可以通过过表达bcl 2蛋白家族或添加提高cAMP水平的药物来实现，cAMP保护抗由渥曼青霉素或星形孢菌素诱导的细胞凋亡。通过显示特异性激动剂（Sp）cAMPS的保护作用和拮抗剂（Rp）cAMPS的增加的杀伤作用，证实了对cAMP的特异性。然而，cAMP没有保护神经酰胺杀死，这表明在神经元细胞中至少有两个主要的凋亡途径。
The apoptotic response of the immature E-cell to the cross-linking of surface IgM receptors provides a good model for cell death and we show in WEHI-231 B-cells that the time course of apoptosis corresponds to the increased formation of ceramide, as measured either by mass (using the diacylglycerol kinase method) or radiolabelling with [H-3]palmitate. inhibitors of sphingosine biosynthesis have no effect on cell death induced by anti-IgM in WEHI-231 but inhibitors of ceramidase accelerate apoptosis, suggesting that activation of sphingomyelinase is the key event in apoptosis. We have demonstrated this by in vitro assay of neutral sphingomyelinase. Apoptosis is also important in normal brain development and neuronal survival is dependent upon phosphatidylinositol 3-kinase (PI3-kinase) activation by growth factors (insulin, nerve growth factor etc.). Withdrawal of these growth factors or inhibition of PI3-kinase with wortmannin or LY294002 activated the pro-apoptotic CPP32 (Yama/Apopain/caspase 3, EC 3.4.22), activated neutral sphingomyelinase and increased ceramide formation in an immortalized dorsal root ganglion cell line F-ll. Protection against apoptosis can be achieved by overexpression of the bcl2 family of proteins or addition of drugs which elevate cAMP levels, cAMP protects against apoptosis induced by either wortmannin or staurosporine. The specificity for cAMP was confirmed by showing protection with the specific agonist (Sp)cAMPS and increased killing with the antagonist (Rp)cAMPS. However, cAMP did not protect against ceramide killing, suggesting that there are at least two major pathways of apoptosis in neuronal cells.