p53-dependent ceramide response to genotoxic stress
p53-dependent ceramide response to genotoxic stress
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DOI：
10.1172/jci1180
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发表时间：
1998-07-15
影响因子：
15.9
通讯作者：
Hannun, YA
中科院分区：
文献类型：
--
作者：
Dbaibo, GS;Pushkareva, MY;Hannun, YA
p53和神经酰胺都参与了生长抑制的调节，p53被认为是“基因组的守护者”，神经酰胺被认为是“肿瘤抑制脂质”。这两种分子似乎调节细胞周期阻滞、衰老和凋亡。在本研究中，我们研究了p53与神经酰胺的关系。我们发现，用低浓度放线菌素D或γ辐照处理Molt-4细胞（可激活p53依赖性凋亡），仅在p53表达正常水平的细胞中诱导凋亡。在这些细胞中，p53激活后，内源性神经酰胺水平随剂量和时间的增加而增加，这在缺乏功能p53的细胞中没有观察到。在辐照的L929细胞中也观察到类似的结果，其中p53缺陷克隆对辐照的抵抗力明显增强，并且没有神经酰胺反应。然而，在不依赖p53的系统中，如tnf - α诱导的生长抑制或血清剥夺，神经酰胺的积累与p53的上调无关，这表明p53仅在一小部分生长抑制途径中调节神经酰胺的积累。最后，神经酰胺在抑制生长的浓度下使用时不会增加p53水平。此外，当由于人乳头瘤病毒E6蛋白突变或表达而缺乏功能性p53的细胞用外源性神经酰胺处理时，与表达正常p53的细胞相比，存在相同的生长抑制、细胞周期阻滞和凋亡。这些结果表明p53不太可能在神经酰胺的“下游”起作用。相反，他们认为，在p53发挥关键调节作用的情况下，比如对基因毒性应激的反应，它在神经酰胺的“上游”起作用。这些研究开始确定这两种生长抑制途径之间的关系。
Both p53 and ceramide have been implicated in the regulation of growth suppression, p53 has been proposed as the "guardian of the genome" and ceramide has been suggested as a "tumor suppressor lipid." Both molecules appear to regulate cell cycle arrest, senescence, and apoptosis. In this study, we investigated the relationship between p53 and ceramide. We found that treatment of Molt-4 cells with low concentrations of actinomycin D or gamma-irradiation, which activate p53-dependent apoptosis, induces apoptosis only in cells expressing normal levels of p53. In these cells, p53 activation was followed by a dose- and time-dependent increase in endogenous ceramide levels which was not seen in cells lacking functional p53 and treated similarly. Similar results were seen in irradiated L929 cells whereby the p53-deficient clone was significantly more resistant to irradiation and exhibited no ceramide response. However, in p53-independent systems, such as growth suppression induced by TNF-alpha or serum deprivation, ceramide accumulated irrespective of the upregulation of p53, indicating that p53 regulates ceramide accumulation in only a subset of growth-suppressive pathways. Finally, ceramide did not increase p53 levels when used at growth-suppressive concentrations. Also, when cells lacking functional p53, either due to mutation or the expression of the E6 protein of human papilloma virus, were treated with exogenous ceramide, there was equal growth suppression, cell cycle arrest, and apoptosis as compared with cells expressing normal p53. These results indicate that p53 is unlikely to function "downstream" of ceramide. Instead, they suggest that, in situations where p53 performs a critical regulatory role, such as the response to genotoxic stress, it functions "upstream" of ceramide. These studies begin to define a relationship between these two pathways of growth inhibition.