Signaling Mechanisms of TCDD-induced AHR Activation

描述（由申请方提供）：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）毒性效应中的作用。二恶英是一种广泛分布的环境污染物，对动物和人类产生多种特定物种的毒性作用，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溶质芳烃受体（AHR）的激活介导的，该受体作为配体激活的转录因子发挥作用，其纯合消融保护小鼠免受二恶英毒性。二恶英是非遗传毒性的，并且像其他肿瘤促进剂一样，被认为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其作用。MAPKs是许多信号转导途径的主要效应子。然而，二恶英激活的信号通路和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，因为它们的抑制导致AHR功能受损。此外，特定的MAP激酶模块以组织特异性方式调节Ah受体功能。本研究将验证二恶英诱导的MAP激酶通路作为转录因子调节Ah受体活性和功能的假说。我们将集中在分子识别的信号因子参与二恶英对MAPK的作用，MAP激酶介导的AH受体激活的机制的表征和二恶英诱导的AHR功能的分析由培养细胞中的MAPK和MAPK途径的信号因子缺乏的小鼠中的MAPK调节。为了实现这些目标，我们将使用新的方法，将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。从这项工作的结果将进一步我们的了解二恶英引起的生物途径之间的交叉谈判，将确定分子因素的二恶英的不同毒性作用的关键，并将有助于确定其预防的主要候选目标。了解负责AHR激活二恶英的信号机制将提供丰富的信息，立即适用于400多个环境毒物和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.