Up-regulation of Siah1 by ethanol triggers apoptosis in neural crest cells through p38 MAPK-mediated activation of p53 signaling pathway.
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.
Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY, 40292, USA.|University of Louisville Alcohol Research Center, Louisville, KY, 40292, USA.
Fuqiang
F
Yuan
Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY, 40292, USA.|University of Louisville Alcohol Research Center, Louisville, KY, 40292, USA.
Xiaopan
X
Chen
Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY, 40292, USA.|University of Louisville Alcohol Research Center, Louisville, KY, 40292, USA.
Jie
J
Liu
Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY, 40292, USA.|University of Louisville Alcohol Research Center, Louisville, KY, 40292, USA.|Department of Medicine, University of Louisville, Louisville, KY, 40292, USA.
Wenke
W
Feng
Ben May Department for Cancer Research, University of Chicago, Chicago, IL, 60637, USA.
Xiaoyang
X
Wu
Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY, 40292, USA. shaoyu.chen@louisville.edu.|University of Louisville Alcohol Research Center, Louisville, KY, 40292, USA. shaoyu.chen@louisville.edu.
Shao-Yu
SY
Chen
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D000431:Ethanol / Q000633:toxicity*; D051379:Mice; D009432:Neural Crest / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D055550:Protein Stability; D011506:Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D015854:Up-Regulation / Q000187:drug effects; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; C494773:Bak1 protein, mouse; C488588:PUMA protein, mouse; D011506:Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D050998:bcl-2 Homologous Antagonist-Killer Protein; D000431:Ethanol; C484442:Siah1a protein, mouse; D044767:Ubiquitin-Protein Ligases; D048051:p38 Mitogen-Activated Protein Kinases
Apoptosis; Ethanol; Fetal alcohol spectrum disorders; Siah1; p38 MAPK; p53