Walisser Jacqueline A, Bunger Maureen K, Glover Edward, Harstad Eric B, Bradfield Christopher A
McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, Madison, Wisconsin 53706, USA.
J Biol Chem. 2004 Apr 16;279(16):16326-31. doi: 10.1074/jbc.M400784200. Epub 2004 Feb 5.
The Ah receptor nuclear translocator (ARNT) is the dimeric partner of hypoxia-inducible factors and thus plays a pivotal role in cellular adaptation to low oxygen environments. ARNT is also a dimeric partner for the Ah receptor (AHR), and this complex is essential in regulating the adaptive metabolic response to polycyclic aromatic hydrocarbons. Because of the essential role of ARNT in hypoxia-driven developmental events, it has been difficult to study the physiological significance of AHR.ARNT heterodimers in vivo. To address this issue, we developed a hypomorphic Arnt allele that displayed normal development and allowed the examination of the role of ARNT in AHR biology. In this regard, the AHR is also known to mediate two additional biological processes: the toxicological response to compounds such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) and the developmental closure of a fetal vascular structure known as the ductus venosus. Although the mechanism of the adaptive pathway has been well described, the mechanism of AHR-mediated signal transduction in the toxic and developmental pathways is not well understood. Liver perfusion studies demonstrated that ARNT hypomorphs have a patent ductus venosus, identical to that observed in the Ahr null mice. Parallel dioxin toxicity studies demonstrated that the ARNT hypomorphs exhibited resistance to the end points of dioxin exposure. Moreover, we observed that toxicity could be segregated from the classical adaptive responses such as P4501A induction. Taken in sum, these experiments demonstrate that ARNT is an essential component of AHR developmental signaling and shed light on the mechanism of dioxin toxicity.
芳烃受体核转运蛋白（ARNT）是缺氧诱导因子的二聚体伴侣，因此在细胞适应低氧环境中起关键作用。ARNT也是芳烃受体（AHR）的二聚体伴侣，这种复合物对于调节对多环芳烃的适应性代谢反应至关重要。由于ARNT在缺氧驱动的发育事件中起着重要作用，因此很难在体内研究AHR-ARNT异二聚体的生理意义。为了解决这个问题，我们开发了一种低表达的Arnt等位基因，它表现出正常发育，并能够研究ARNT在AHR生物学中的作用。在这方面，已知AHR还介导另外两个生物学过程：对2,3,7,8-四氯二苯并对二恶英（二恶英）等化合物的毒理学反应以及胎儿血管结构（即静脉导管）的发育闭合。虽然适应性途径的机制已经得到很好的描述，但AHR介导的毒性和发育途径中的信号转导机制尚不清楚。肝脏灌注研究表明，ARNT低表达小鼠有开放的静脉导管，这与在Ahr基因敲除小鼠中观察到的情况相同。平行的二恶英毒性研究表明，ARNT低表达小鼠对二恶英暴露的终点表现出抗性。此外，我们观察到毒性可以与经典的适应性反应（如细胞色素P4501A诱导）区分开来。综上所述，这些实验表明ARNT是AHR发育信号传导的重要组成部分，并揭示了二恶英毒性的机制。
