Alkaline ceramidase 2 is a novel direct target of p53 and induces autophagy and apoptosis through ROS generation.
Alkaline ceramidase 2 is a novel direct target of p53 and induces autophagy and apoptosis through ROS generation.
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碱性神经酰胺酶 2 是 p53 的新型直接靶标，通过 ROS 生成诱导自噬和细胞凋亡
DOI：
10.1038/srep44573
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发表时间：
2017-03-15
影响因子：
4.6
通讯作者：
Bu Y
中科院分区：
文献类型：
--
作者：
Wang Y;Zhang C;Jin Y;Wang;He Q;Liu Z;Ai Q;Lei Y;Li Y;Song F;Bu Y
ACER2是一种关键的鞘磷脂代谢酶，已被证明在DNA损伤等各种刺激下显著上调。然而，ACER2基因的转录调控机制及其在自噬调控中的潜在作用尚不清楚。在本研究中，我们首次鉴定了人类ACER2基因的启动子，并发现人类ACER2的转录受P53的直接调控，并且ACER2参与了自噬和细胞凋亡的诱导。一系列荧光素酶报告分析表明，ACER2主要启动子位于其第一内含子内，存在共识的P53结合位点。一致地，强制表达P53显著刺激ACER2转录。值得注意的是，ACER2显著增强了P53介导的自噬和细胞凋亡。去除必需的自噬基因ATG5表明，ACER2诱导的自噬促进了其对细胞凋亡的影响。进一步的研究表明，ACER2介导的自噬和细胞凋亡伴随着ROS的产生。综上所述，我们目前的研究有力地表明，ACER2在P53诱导的自噬和凋亡中起着关键作用，因此可能成为治疗癌症的一个新的和有吸引力的分子靶点。
ACER2 is a critical sphingolipid metabolizing enzyme, and has been shown to be remarkably up-regulated following various stimuli such as DNA damage. However, the transcriptional regulatory mechanism of ACER2 gene and its potential role in the regulation of autophagy remain unknown. In this study, we have for the first time identified the human ACER2 gene promoter, and found that human ACER2 transcription is directly regulated by p53 and ACER2 is implicated in the induction of autophagy as well as apoptosis. A series of luciferase reporter assay demonstrated that ACER2 major promoter is located within its first intron where the consensus p53-binding sites exist. Consistently, forced expression of p53 significantly stimulated ACER2 transcription. Notably, p53-mediated autophagy and apoptosis were markedly enhanced by ACER2. Depletion of the essential autophagy gene ATG5 revealed that ACER2-induced autophagy facilitates its effect on apoptosis. Further studies clearly showed that ACER2-mediated autophagy and apoptosis are accompanied by ROS generation. In summary, our present study strongly suggests that ACER2 plays a pivotal role in p53-induced autophagy and apoptosis, and thus might serve as a novel and attractive molecular target for cancer treatment.