Signaling Mechanisms of TCDD-induced AHR Activation

描述（由申请人提供）：本研究的长期目标是了解丝裂原活化蛋白激酶（MAPK）信号通路在2,3,7,8-四氯二苯并-对二恶英（TCDD）毒性作用中的作用。二恶英是一种广泛传播的环境污染物，对动物和人类具有多种物种特异性毒性，包括免疫、生殖和发育毒性、癌症、消耗综合征和死亡。二恶英毒性是由细胞质芳香烃受体（AHR）的激活介导的，AHR作为配体激活的转录因子，其纯合子消融保护小鼠免受二恶英毒性的影响。二恶英是无基因毒性的，像其他肿瘤促进剂一样，被认为是通过促进最终负责细胞增殖和细胞存活的信号通路来发挥作用的。MAPKs是许多这些信号转导途径的主要效应器。然而，二恶英激活的信号通路与AHR功能之间的分子联系尚未建立。二恶英诱导的MAPKs在Ah受体激活中起重要作用，因为它们的抑制会导致AHR功能受损。此外，特定的MAP激酶模块以组织特异性的方式调节Ah受体的功能。本研究将验证二恶英诱导的MAP激酶通路作为转录因子调控Ah受体活性和功能的假说。我们将重点研究二恶英作用于MAPK的信号因子的分子鉴定，MAP激酶介导Ah受体激活的机制，以及在培养细胞和MAPK通路信号因子缺乏的小鼠中，二恶英诱导的由MAPK调控的AHR功能。为了实现这些目标，我们将使用新的方法，将对信号转导途径的理解与毒性反应的分子生物学分析结合起来。这项工作的结果将进一步加深我们对二恶英引发的生物途径之间的交叉对话的理解，将确定二恶英各种毒性作用的关键分子因素，并将有助于确定其预防的主要候选靶点。了解二恶英激活AHR的信号机制将提供丰富的信息，可立即应用于400多种环境毒物和Ah受体激动剂的毒性研究，其中二恶英是原型。

DESCRIPTION (provided by applicant): The long-term goal of this study is to understand the role that the mitogen-activated protein kinase (MAPK) signaling pathways play in the toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Dioxin is a widely spread environmental contaminant that exerts diverse species-specific toxic effects in animals and humans, including immune, reproductive and developmental toxicity, cancer, wasting syndrome and death. Dioxin toxicity is mediated by the activation of a cytosolic aromatic hydrocarbon receptor (AHR) that functions as a ligand-activated transcription factor and whose homozygous ablation protects mice from dioxin toxicity. Dioxin is non-genotoxic and, like other tumor promoters, is believed to exert its effects by promoting signaling pathways ultimately responsible for cell proliferation and cell survival. The (MAPKs) are the primary effectors of many of those signal transduction pathways. However, the molecular connections between dioxin-activated signaling pathways and AHR function have yet to be established. Dioxin-induced MAPKs play an important role in Ah receptor activation, because their suppression causes impaired AHR function. In addition, specific MAP kinase modules regulate Ah receptor function in a tissue specific manner. This proposal will test the hypothesis that dioxin-induced MAP kinase pathways regulate the activity and function of Ah receptor as a transcription factor. We will focus on the molecular identification of the signaling factors involved in dioxin action on MAPKs, the characterization of the mechanism of MAP kinase-mediated Ah receptor activation and the analysis of dioxin-induced AHR functions regulated by MAPKs in culture cells and in mice deficient in signaling factors of the MAPK pathways. To achieve these aims, we will use novel approaches that bring together an understanding of signal transduction pathways with the analysis of the molecular biology of the toxic response. Results from this work will further our understanding of cross-talks between dioxin-elicited biological pathways, will identify molecular factors critical for the diverse toxic effects of dioxin and will help characterize primary candidate targets for its prevention. Understanding the signaling mechanisms responsible for AHR activation by dioxin will provide a wealth of information immediately applicable to the study of the toxicity of the more than 400 environmental toxicants and Ah receptor agonists of which dioxin is the prototype.