Signaling Mechanisms of TCDD-induced AHR Activation

TCDD 诱导 AHR 激活的信号机制

• 批准号: 6803611
• 负责人: YING XIA
• 金额: $ 32.81万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6803611
• 关键词: SDS polyacrylamide gel electrophoresis; aromatic hydrocarbon receptor; autoradiography; biological signal transduction; cell proliferation; dioxins; environmental exposure; gel mobility shift assay; gene expression; genetically modified animals; laboratory mouse; ligands; mitogen activated protein kinase; phosphorylation; protein structure function; tissue /cell culture; transcription factor; western blottings

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.

描述（由申请人提供）：本研究的长期目标是了解丝裂原激活蛋白激酶（MAPK）信号通路在 2,3,7,8-四氯二苯并-p- 的毒性作用中所起的作用。二恶英（TCDD）。二恶英是一种广泛传播的环境污染物，对动物和人类产生多种物种特异性毒性作用，包括免疫、生殖和发育毒性、癌症、消耗综合症和死亡。二恶英毒性是通过胞质芳香烃受体（AHR）的激活介导的，该受体作为配体激活的转录因子，其纯合消除可以保护小鼠免受二恶英毒性。二恶英是非基因毒性的，与其他肿瘤促进剂一样，据信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。 (MAPK) 是许多信号转导途径的主要效应器。然而，二恶英激活信号通路与 AHR 功能之间的分子联系尚未建立。二恶英诱导的 MAPK 在 Ah 受体激活中发挥重要作用，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方式调节 Ah 受体功能。该提案将检验二恶英诱导的 MAP 激酶途径调节 Ah 受体作为转录因子的活性和功能的假设。我们将重点关注二恶英对 MAPK 作用的信号转导因子的分子鉴定、MAP 激酶介导的 Ah 受体激活机制的表征以及培养细胞和缺陷小鼠中由 MAPK 调节的二恶英诱导的 AHR 功能的分析。 MAPK 通路的信号因子。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相互作用的理解，将确定对二恶英多种毒性作用至关重要的分子因素，并有助于确定其预防的主要候选目标。了解二恶英激活 AHR 的信号传导机制将为研究 400 多种环境毒物和以二恶英为原型的 Ah 受体激动剂的毒性研究提供大量信息。