Foxa2 may modulate hepatic apoptosis through the cIAP1 pathway
Foxa2 may modulate hepatic apoptosis through the cIAP1 pathway
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DOI：
10.1016/j.cellsig.2012.12.012
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发表时间：
2013-04-01
影响因子：
4.8
通讯作者：
Holterman, Ai-Xuan
中科院分区：
文献类型：
--
作者：
Wang, Kewei;Brems, John J.;Holterman, Ai-Xuan
肝细胞凋亡是慢性肝损伤的普遍特征，但其分子机制尚不清楚。富含肝脏的Foxa2转录因子与炎症和肿瘤有关。FOXA2可能在细胞凋亡的调节中发挥作用。本研究旨在探讨Foxa2与肝细胞凋亡的关系。用半胱氨酸天冬氨酸氨基转移酶(Caspase)活性和原位末端标记法(TUNEL)检测不同诱因诱导的细胞凋亡。结果表明，细胞凋亡损伤与Foxa2基因表达下调有关。FOXA2表达载体减少了细胞的凋亡率，而沉默Foxa2的siRNA增加了细胞的凋亡率。FOXA2与抗凋亡基因cIAP1、cIAP2、XIAP和Survivin的表达谱相关。显著地，沉默Foxa2的siRNA降低了cIAP1的表达，但增加了Foxa2表达载体的表达。EMSA和凝胶超移动实验表明，CIAP1启动子具有与Foxa2核蛋白结合的特异性DNA序列。芯片检测发现，CIAP1启动子也被Foxa2核因子占据。CIAP1启动子中Foxa2结合结构域的缺失显著降低了其启动子活性。结论：Foxa2转录因子调控肝细胞凋亡的机制可能是通过cIAP1信号通路。FOXA2可作为肝病治疗干预的潜在靶点。(C)2012 Elsevier Inc.保留所有权利。
Hepatocyte apoptosis is a ubiquitous feature of chronic liver injury, but the molecular mechanism remains to be determined. The liver-enriched Foxa2 transcription factor has been implicated in inflammation and neoplasia. Foxa2 may play a role in the regulation of apoptosis. This study aimed to investigate the relationship between Foxa2 and hepatic apoptosis. Apoptosis was induced with different causative factors as measured by caspase activity and TUNEL assay. Results showed that the apoptotic injury was associated with a downregulation of Foxa2. Foxa2-expressing vectors decreased apoptosis, whereas siRNA silencing of Foxa2 increased apoptosis in HepG2 cells. Foxa2 was correlated with expression profiling of anti-apoptotic genes cIAP1, cIAP2, XIAP, and survivin. Significantly, the cIAP1 expression was decreased by siRNA silencing of Foxa2, but increased by Foxa2-expressing vectors. The promoter of cIAP1 had specific DNA sequences that could be bound by Foxa2 nuclear protein as demonstrated by EMSA and gel supershift assay. The cIAP1 promoter was also occupied by Foxa2 nuclear factor through ChIP assay. Deletion of putative Foxa2 binding domains in cIAP1 promoter significantly reduced its promoter activity.Conclusion: A mechanism by which Foxa2 transcription factor modulates hepatic apoptosis may be through cIAP1 signaling pathway. Foxa2 can be a potential target for therapeutic intervention in liver diseases. (C) 2012 Elsevier Inc. All rights reserved.