Abnormal liver development and resistance to 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity in mice carrying a mutation in the DNA-binding domain of the aryl hydrocarbon receptor.
Abnormal liver development and resistance to 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity in mice carrying a mutation in the DNA-binding domain of the aryl hydrocarbon receptor.
复制标题
DOI：
10.1093/toxsci/kfn149
复制
发表时间：
2008-11
期刊：
影响因子：
--
通讯作者：
Bradfield CA
中科院分区：
文献类型：
--
作者：
Bunger MK;Glover E;Moran SM;Walisser JA;Lahvis GP;Hsu EL;Bradfield CA
芳烃受体（AHR）因其在对大量环境污染物的适应性和毒性反应中的作用以及在肝血管发育中的作用而闻名。经典的AHR途径包括配体结合、核易位、与AHR核易位子（ARNT）的异源二聚体结合以及异源二聚体与二恶英反应元件（DREs）的结合，从而调节一系列基因的转录。AHR还与核定位和DNA结合之外的信号转导事件有关，并且有研究表明，这些信号转导途径可能在2,3,7,8-四氯二苯并-对二恶英（TCDD）的毒性中发挥重要作用。在这里，我们报道了一种表达AHR蛋白的小鼠模型，该蛋白能够与配体结合，与伴侣蛋白相互作用，与ARNT的功能性异二聚化和核易位，但不能与DREs结合。使用该模型，我们提供了证据，证明DNA结合是Ahr介导的肝脏发育所必需的，因为Ahrdbd/dbd小鼠表现出静脉导管未闭，类似于Ahr - / -小鼠。此外，Ahrdbd/dbd小鼠在所有测试终点均对tcdd诱导的毒性具有抗性。这些数据表明，DNA结合对于ahr介导的发育和毒性信号传导是必要的。
The aryl hydrocarbon receptor (AHR) is known for its role in the adaptive and toxic responses to a large number of environmental contaminants, as well as its role in hepatovascular development. The classical AHR pathway involves ligand binding, nuclear translocation, heterodimerization with the AHR nuclear translocator (ARNT), and binding of the heterodimer to dioxin response elements (DREs), thereby modulating the transcription of an array of genes. The AHR has also been implicated in signaling events independent of nuclear localization and DNA binding, and it has been suggested that such pathways may play important roles in the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Here, we report the generation of a mouse model that expresses an AHR protein capable of ligand binding, interactions with chaperone proteins, functional heterodimerization with ARNT, and nuclear translocation, but is unable to bind DREs. Using this model, we provide evidence that DNA binding is required AHR-mediated liver development, as Ahrdbd/dbd mice exhibit a patent ductus venosus, similar to what is seen in Ahr−/− mice. Furthermore, Ahrdbd/dbd mice are resistant to TCDD-induced toxicity for all endpoints tested. These data suggest that DNA binding is necessary for AHR-mediated developmental and toxic signaling.
登录
查看更多内容
DOI：
10.1073/pnas.190256997
发表时间：
2000-09-12
影响因子：
11.1
作者：
Lahvis, GP;Lindell, SL;Bradfield, CA
通讯作者：
Bradfield, CA
影响因子：
4.8
作者：
Ge, NL;Elferink, CJ
通讯作者：
Elferink, CJ
影响因子：
4.8
作者：
Bunger, MK;Moran, SM;Bradfield, CA
通讯作者：
Bradfield, CA
影响因子：
4.8
作者：
Carver, LA;LaPres, JJ;Bradfield, CA
通讯作者：
Bradfield, CA
DOI：
10.1073/pnas.93.4.1671
发表时间：
1996-02-20
影响因子：
11.1
作者：
Liang, HCL;Li, H;Nebert, DW
通讯作者：
Nebert, DW