Untersuchung des Zusammenspiels zwischen Estrogenrezeptoren und AhR nuclear translocator (ARNT).

雌激素是类固醇激素，调节许多重要的生理过程。它们的作用是由两个雌激素受体(ER)介导的，ER？和ER？在配体结合后调节靶基因的表达。环境中的污染物会干扰ERs的功能，从而对人体造成有害影响。其中一种污染物是二恶英，它是一种通过不完全燃烧废物而形成的环境污染物。二恶英的生物学效应是由芳烃受体(AhR)介导的，该受体属于碱性螺旋-环-螺旋(BHLH)-PAS转录调节家族。为了变得活跃，AhR不仅必须与二恶英结合，而且还必须与其合作伙伴AhR核转运蛋白(ARNT)结合，这是另一种bHLH-PAS蛋白。最近的研究表明，ArnT还可以作为ER的共同激活剂，即增加ArnT的量可以增强ER的活性。这一发现表明，二恶英对ER功能的干扰至少部分是由于ER和AhR之间对共同的共激活因子Arnt的竞争。这个项目的目的是通过阐明ARNT和ER之间的相互作用来研究这一假说。要做到这一点，首先要检测Arnt的上调和下调是否影响二恶英对ER功能的影响，其次要研究Arnt-ER相互作用中的其他因素，即ER的其他共激活物。这应该会使我们更好地了解二恶英的有害影响，并可能拓宽我们对环境污染物一般行为的了解。

Estrogens are steroid hormones and regulate many vital physiological processes. Their effects are mediated by two estrogen receptors (ER), ER¿ and ERß which regulate expression of target genes following binding of the ligand. Contaminants in the environment can interfere with the function of ERs and thereby cause deleterious effects in the body. One such contaminant is dioxin which is an environmental pollutant formed through incomplete combustion of waste. The biological effects of dioxin are mediated by the Aryl hydrocarbon receptor (AhR) that belongs to the family of basic helix-loop-helix (bHLH)-PAS transcriptional regulators. To become active, AhR must not only bind to dioxin but additionally to its partner AhR nuclear translocator (ARNT), another bHLH-PAS protein. Recently, it has been shown that ARNT can also act as co-activator of ER, i.e. increased amounts of ARNT enhance ER activity. This finding suggests that the interference of dioxin with the ER function is at least partly due to a competition between ER and AhR for the common co-activator ARNT. The aim of this project is to investigate this hypothesis by elucidating the interplay between ARNT and ER. This should be achieved by firstly testing whether ARNT up- and down-regulation affects the effects of dioxin on ER function, and secondly investigating the involvement of additional factors in the ARNT-ER interplay, namely other co-activators of ER. This should lead to a better understanding of the harmful effects of dioxin and might broaden our knowledge about the action of environmental contaminants in general.