Up-regulation of Siah1 by ethanol triggers apoptosis in neural crest cells through p38 MAPK-mediated activation of p53 signaling pathway.
Up-regulation of Siah1 by ethanol triggers apoptosis in neural crest cells through p38 MAPK-mediated activation of p53 signaling pathway.
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DOI：
10.1007/s00204-016-1746-3
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发表时间：
2017-02
影响因子：
6.1
通讯作者：
Chen SY
中科院分区：
文献类型：
--
作者：
Yuan F;Chen X;Liu J;Feng W;Wu X;Chen SY
SIAH1是E3泛素连接酶中的一种，在调节靶蛋白降解中起关键作用。本研究旨在验证Siah1通过p38 MAPK介导的p53信号通路激活介导乙醇诱导的NCC细胞凋亡的假设。我们发现NCC暴露于乙醇导致p53的总蛋白水平和p53在丝氨酸15处的磷酸化增加。乙醇暴露也导致p38 MAPK磷酸化的显著增加。敲低Siah1显著降低了乙醇诱导的p38 MAPK磷酸化的增加。siRNA敲低Siah1或siRNA或抑制剂下调p38 MAPK显著减少乙醇诱导的p53积累和p53磷酸化。此外，乙醇暴露导致NCC中p53下游靶点的表达和细胞凋亡显著增加，这可以通过siRNA下调Siah1而显著减少。通过siRNA敲低p38 MAPK也显著减少乙醇诱导的细胞凋亡。这些结果表明Siah1在乙醇诱导的NCC细胞凋亡中起着至关重要的作用，并且乙醇上调Siah1可以通过p38 MAPK介导的p53信号通路的激活来触发细胞凋亡。
Seven in absentia homolog 1 (SIAH1) is one of the E3 ubiquitin ligases and plays a key role in regulating target protein degradation. This study was designed to test the hypothesis that Siah1 mediates ethanol-induced apoptosis in NCCs through p38 MAPK-mediated activation of the p53 signaling pathway. We found that exposure of NCCs to ethanol resulted in the increases in the total protein levels of p53 and the phosphorylation of p53 at serine 15. Ethanol exposure also resulted in a significant increase in the phosphorylation of p38 MAPK. Knock-down of Siah1 dramatically reduced the ethanol-induced increase in the phosphorylation of p38 MAPK. Knock-down of Siah1 by siRNA or down-regulation of p38 MAPK by either siRNA or inhibitor significantly diminished ethanol-induced accumulations of p53 and the phosphorylation of p53. In addition, ethanol exposure resulted in a significant increase in the expression of p53 downstream targets and apoptosis in NCCs, which can be significantly diminished by down-regulation of Siah1 with siRNA. Knock-down of p38 MAPK by siRNA also dramatically reduced the ethanol-induced apoptosis. These results demonstrate that Siah1 plays a crucial role in ethanol-induced apoptosis in NCCs and that the up-regulation of Siah1 by ethanol can trigger apoptosis through p38 MAPK-mediated activation of the p53 signaling pathway.