Billis W, Fuks Z, Kolesnick R
Laboratory of Signal Transduction, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Recent Prog Horm Res. 1998;53:85-92; discussion 93.
Exposure of mammalian cells to ionizing radiation leads primarily to DNA damage-induced cell death. The induction of apoptosis by ionizing radiation represents an alternative mode to cell kill. Breakdown of sphingomyelin to produce ceramide by activation of sphingomyelinase is one of the upstream signalling cascades activated in apoptotic cells in response to stimuli such as TNF. Using genetic models of acid sphingomyelinase deficiency, the ceramide generated by radiation-induced activation of sphingomyelinase has been shown to serve as a second messenger in initiating an apoptotic response. PKC activation represents an upstream anti-apoptotic checkpoint at the sphingomyelinase level as well as a checkpoint downstream of ceramide generation. The balance between these pro- and anti-apoptotic systems may determine the magnitude of the observed apoptotic response.
哺乳动物细胞暴露于电离辐射主要会导致DNA损伤诱导的细胞死亡。电离辐射诱导的细胞凋亡是细胞杀伤的另一种方式。通过鞘磷脂酶激活将鞘磷脂分解产生神经酰胺是凋亡细胞中响应诸如肿瘤坏死因子等刺激而激活的上游信号级联反应之一。利用酸性鞘磷脂酶缺陷的遗传模型，已表明辐射诱导的鞘磷脂酶激活所产生的神经酰胺在启动凋亡反应中作为第二信使发挥作用。蛋白激酶C的激活代表了鞘磷脂酶水平的上游抗凋亡检查点以及神经酰胺产生下游的检查点。这些促凋亡和抗凋亡系统之间的平衡可能决定所观察到的凋亡反应的程度。
