Deciphering posttranslational codes of the dioxin receptor

破译二恶英受体的翻译后密码

• 批准号: nhmrc : 453687
• 负责人: Prof Jeffrey Gorman
• 金额: $ 36.01万
• 依托单位: The University of Adelaide
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2007
• 资助国家: 澳大利亚
• 起止时间: 2007-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/deciphering-posttranslational-codes-dioxin-receptor/95006
• 关键词: Deciphering; posttranslational; codes; dioxin; receptor

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.

二恶英受体（DR）是一种蛋白质，通过结合外源性物质（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，它就变成了一种活跃的基因调节蛋白，开启了参与外源性物质分解和排泄的基因。最近发现DR还执行其他与异生物质分解无关的重要功能。这些包括胚胎肝脏中的血管发育和发情周期中的激素产生。这些观察结果表明，自然的生理机制也存在激活DR，为它提供了一个单独的代码来执行这些先天功能。一些人造化学品，如二恶英和多氯联苯，特别擅长激活DR。然而，它们具有氯化的化学结构，不会被保护系统分解。这产生了广泛的严重毒性反应。已经确定毒性是由DR的持续过度激活引起的，但是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可以被正常细胞信号系统激活，这会诱导蛋白质的不同修饰（不同的密码）。我们正在将这种修改代码与能够被分解的外源性物质和抗分解的二恶英诱导的修改代码进行比较。我们假设，二恶英会给一个过度的代码激活修改，导致在不受控制的调节基因在发育和外源性分解途径。我们将探讨这一假设，即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。