Up-regulation of Siah1 by ethanol triggers apoptosis in neural crest cells through p38 MAPK-mediated activation of p53 signaling pathway

• Published in: Archives of toxicology Vol. 91; no. 2; pp. 775 - 784
• Main Authors: Yuan, Fuqiang, Chen, Xiaopan, Liu, Jie, Feng, Wenke, Wu, Xiaoyang, Chen, Shao-yu
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.02.2017; Springer Nature B.V
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; Apoptosis - physiology; Apoptosis Regulatory Proteins - metabolism; bcl-2 Homologous Antagonist-Killer Protein - metabolism; Biomedical and Life Sciences; Biomedicine; Environmental Health; Enzyme Activation - drug effects; Ethanol; Ethanol - toxicity; Gene expression; Mice; Molecular Toxicology; Neural Crest - cytology; Neural Crest - drug effects; Neural Crest - metabolism; Neurons; Occupational Medicine/Industrial Medicine; p38 Mitogen-Activated Protein Kinases - metabolism; Pharmacology/Toxicology; Phosphorylation - drug effects; Protein Stability; Proteins - metabolism; Signal transduction; Signal Transduction - drug effects; Toxicity; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Proteins - metabolism; Up-Regulation - drug effects; Fetal alcohol spectrum disorders; Ethanol; p38 MAPK; Siah1; Apoptosis; p53
• ISSN: 0340-5761; 1432-0738
• DOI: 10.1007/s00204-016-1746-3

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.