Resistance to 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity and abnormal liver development in mice carrying a mutation in the nuclear localization sequence of the aryl hydrocarbon receptor
Resistance to 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity and abnormal liver development in mice carrying a mutation in the nuclear localization sequence of the aryl hydrocarbon receptor
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DOI：
10.1074/jbc.m209594200
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发表时间：
2003-05-16
影响因子：
4.8
通讯作者：
Bradfield, CA
中科院分区：
文献类型：
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作者：
Bunger, MK;Moran, SM;Bradfield, CA
Ah 受体 (AHR) 介导对许多平面芳香族化学物质的代谢适应。这种适应性机制的基本步骤包括胞浆中配体的 AHR 结合、受体易位至细胞核、与 Ah 受体核转位子二聚化，以及该异二聚体转录因子与启动子上游的二恶英响应元件 (DRE) 结合，调节参与外源代谢的基因的表达。 AHR 还涉及哺乳动物生物学的其他方面，例如 2,3,7,8-四氯二苯并-对二恶英等分子的毒性以及正常肝脏发育的调节。为了测试这些额外的 AHR 介导的过程是否需要核事件，例如 DRE 结合，我们使用同源重组来产生 AHR 核定位/DRE 结合域突变的小鼠。发现这些 Ahr(nls) 小鼠对我们检查的所有 2,3,7,8-四氯二苯并-对二恶英诱导的毒性反应具有抵抗力，包括肝肿大、胸腺退化和腭裂形成。此外，在这些小鼠中观察到的肝脏发育异常与在 Ahr 基因座带有无效等位基因的小鼠中观察到的肝脏发育异常相同。总而言之，这些数据支持一个模型，其中大多数（如果不是全部）AHR 调节的生物学都需要核定位。
The Ah receptor (AHR) mediates the metabolic adaptation to a number of planar aromatic chemicals. Essential steps in this adaptive mechanism include AHR binding of ligand in the cytosol, translocation of the receptor to the nucleus, dimerization with the Ah receptor nuclear translocator, and binding of this heterodimeric transcription factor to dioxin-responsive elements (DREs) upstream of promoters that regulate the expression of genes involved in xenobiotic metabolism. The AHR is also involved in other aspects of mammalian biology, such as the toxicity of molecules like 2,3,7,8-tetrachlorodibenzo-p-dioxin as well as regulation of normal liver development. In an effort to test whether these additional AHR-mediated processes require a nuclear event, such as DRE binding, we used homologous recombination to generate mice with a mutation in the AHR nuclear localization/DRE binding domain. These Ahr(nls) mice were found to be resistant to all 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced toxic responses that we examined, including hepatomegaly, thymic involution, and cleft palate formation. Moreover, aberrations in liver development observed in these mice were identical to that observed in mice harboring a null allele at the Ahr locus. Taken in sum, these data support a model where most, if not all, of AHR-regulated biology requires nuclear localization.