Identification of Stanniocalcin 2 as a Novel Aryl Hydrocarbon Receptor Target Gene
Identification of Stanniocalcin 2 as a Novel Aryl Hydrocarbon Receptor Target Gene
复制标题
DOI：
10.1124/jpet.112.201111
复制
发表时间：
2013-03-01
影响因子：
3.5
通讯作者：
Elferink, Cornelis J.
中科院分区：
文献类型：
--
作者：
Harper, Tod A., Jr.;Joshi, Aditya D.;Elferink, Cornelis J.
正常的肝细胞功能对生存至关重要；因此，未修复的实质组织破坏导致肝脏失代偿是毁灭性的。因此，了解调节肝再生的动态平衡过程具有重要的临床意义，而芳香烃受体(AhR)在固有的凋亡刺激后能够促进细胞存活的证据是再生过程中不可或缺的。目前的研究使用原代肝细胞来确定符合正常AhR生物学的生存机制。利用Cre-lox系统来操纵AhR的状态，我们设计了一个全面的微阵列分析来识别伴随AhR丢失而来的转录组的直接和直接变化。结果，我们确定了一个独特的数据集，与之前的阵列研究相比，重叠最少，最终确定Stanniocalcin 2(Stc2)是一个新的受体靶基因，先前报道在内质网应激中具有细胞保护作用。Stc2启动子包含多个可能的异源反应元件，聚集在一个250个碱基的区域，通过染色质免疫沉淀招募AhR。有趣的是，Stc2基因的表达对经典的外源性AhR激动剂是无效的，但以一种AhR依赖的机制响应细胞压力，这一机制与促进细胞存活的过程一致。
Proper hepatocyte function is vital for survival; thus, unrepaired destruction of the parenchymal tissue leading to liver decompensation is devastating. Therefore, understanding the homeostatic process regulating liver regeneration is clinically important, and evidence that the aryl hydrocarbon receptor (AhR) can promote cell survival after intrinsic apoptotic stimuli is integral to the regenerative process. The current study uses primary hepatocytes to identify survival mechanisms consistent with normal AhR biology. Taking advantage of the Cre-lox system to manipulate AhR status, we designed a comprehensive microarray analysis to identify immediate and direct changes in the transcriptome concomitant with the loss of the AhR. As a result, we identified a unique data set with minimal overlap, compared with previous array studies, culminating in the identification of Stanniocalcin 2 (Stc2) as a novel receptor target gene previously reported to have a cytoprotective role in endoplasmic reticulum stress. The Stc2 promoter contains multiple putative xenobiotic response elements clustered in a 250-bp region that was shown to recruit the AhR by chromatin immunoprecipitation. Of interest, Stc2 gene expression is refractory to classic exogenous AhR agonists, but responds to cellular stress in an AhR-dependent mechanism consistent with a process promoting cell survival.