Deciphering posttranslational codes of the dioxin receptor

二恶英受体（DR）是一种蛋白质，通过结合外源物质（即在食物来源和一般环境中发现的外来或抗营养化学物质）来保护人体细胞。当这些化学物质与DR结合时，DR就变成了一种活跃的基因调节蛋白，开启了参与分解和排泄外源性药物的基因。最近已经发现DR具有与外源性分解无关的其他重要功能。这包括胚胎肝脏的血管发育和发情周期中激素的产生。这些观察结果表明，激活DR的自然生理机制也存在，为其提供了执行这些先天功能的单独代码。许多人造化学物质，如二恶英和多氯联苯，特别善于激活dr。然而，它们具有氯化的化学结构，不能被保护系统分解。这会产生一系列严重的毒性反应。已经确定，毒性是由DR的持续过度激活引起的，但这种过度激活如何诱导毒性结果尚不清楚。由于DR在早期发育和雌激素产生中起作用，本项目将研究DR如何被激活以执行这些功能。我们最初的实验表明，DR可以被正常的细胞信号系统激活，从而诱导蛋白质的不同修饰（不同的代码）。我们正在将这种修改代码与能够被分解的外源性药物和不易被分解的二恶英引起的修改代码进行比较。我们假设二恶英会提供过多的激活修饰代码，导致在发育和外源分解途径中使用的基因无法控制的调节。我们将探讨这种基因调控控制的严重损失是二恶英中毒的多种毒性的基础。

The dioxin receptor (DR) is a protein which protects human cells by binding xenobiotics, ie foreign or anti-nutritional chemicals found in food sources and the general environment. When these chemicals bind the DR, it becomes an active gene regulatory protein, turning on genes that are involved in breakdown and excretion of the xenobiotics. Recently it has been found that the DR performs other important functions which are unrelated to xenobiotic breakdown. These include blood vessel development in the embryonic liver and hormone production during the estrous cycle. These observations imply that natural physiological mechanisms also exist for activating the DR, providing it with a separate code to perform these innate functions. A number of man-made chemicals, such as dioxins and PCBs, are especially good at activating the DR. However, they have chlorinated chemical structures, which are not broken down by the protective system. This creates a wide range of severe toxic responses. It has been established that toxicities result from persistent hyperactivation of the DR, but how this hyperactivation induces the toxic outcomes is not known. As the DR has roles in early development and estrogen production, this project will investigate how the DR becomes activated to perform these functions. Our initial experiments have shown that the DR can be activated by normal cell signalling systems, which induce distinct modifications (a distinct code) to the protein. We are comparing this code of modifications to those induced by xenobiotics which are able to be broken down, and dioxins which are resistant to breakdown. We hypothesise that dioxins will give an excessive code of activating modifications, resulting in uncontrolled regulation of genes used in both the developmental and xenobiotic breakdown pathways. We will explore the hypothesis that this gross loss of gene regulatory control underpins the multifarious toxicities of dioxin poisoning.