Signaling Mechanisms of TCDD-induced AHR Activation

TCDD 诱导 AHR 激活的信号机制

基本信息

批准号：
7263897
负责人：
YING XIA
金额：
$ 31.11万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-30 至 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7263897
关键词：
ARNT protein Ablation Activation Analysis Affect Agonist Animals Aryl Hydrocarbon Receptor Biological CYP1A1 gene CYP1A2 gene CYP1B1 gene Cell Proliferation Cell Survival Cessation of life Complex Cultured Cells Cytochrome P-450 CYP1A1 Cytochrome P450 DNA Binding Development Dimerization Dioxins Dominant-Negative Mutation Embryo Environmental Pollution Enzymes Epidermal Growth Factor Receptor Exhibits Extracellular Signal Regulated Kinases Family Gene Expression Genetic Transcription Goals Human Immune Impairment In Vitro Individual Ink Knowledge Lead Ligands MAP Kinase Kinase Kinase 1 MAP Kinase Modules MAPK8 gene MAPK9 gene Malignant Neoplasms Mediating Mitogen-Activated Protein Kinases Molecular Molecular Biology Mus N-terminal Nuclear Translocation Pathway interactions Phosphorylation Phosphotransferases Play Post-Translational Protein Processing Prevention Receptor Activation Regulation Research Personnel Role Signal Pathway Signal Transduction Signal Transduction Pathway Specificity Testing Tetrachlorodibenzodioxin Tissues Toxic Environmental Substances Toxic effect Tumor Promoters Wasting Syndrome Work activating transcription factor aromatic hydrocarbon receptor carcinogenicity congenic cytosolic receptor hepatoma cell human MAP3K1 protein in vivo inhibitor/antagonist member novel strategies programs prototype receptor receptor function reproductive response transcription factor

项目摘要

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）：这项研究的长期目标是了解有丝分裂原激活的蛋白激酶（MAPK）信号通路在2,3,7,8-二甲苯二甲苯的毒性作用中起作用的作用。二恶英（TCDD）。二恶英是一种广泛传播的环境污染物，在动物和人类中发挥各种物种特异性毒性作用，包括免疫，生殖和发育毒性，癌症，浪费综合征和死亡。二恶英毒性是通过充当配体激活的转录因子的胞质芳基烃受体（AHR）的激活来介导的，其纯合消融可保护小鼠免受二恶英毒性的侵害。二恶英是非生物毒性的，与其他肿瘤启动子一样，二恶英被认为通过促进信号通路最终导致细胞增殖和细胞存活来发挥作用。（MAPK）是许多信号转导途径的主要效应子。但是，尚未建立二恶英激活信号通路和AHR功能之间的分子连接。二恶英诱导的MAPK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激酶模块以组织特定方式调节AH受体功能。该建议将检验以下假设：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。我们将重点介绍对MAPK涉及的二恶英作用的信号传导因子的分子鉴定，MAP激酶介导的AH受体激活机理的表征以及对培养细胞中MAPK调节的二恶英诱导的AHR功能的分析，而小鼠不足在MAPK途径的信号因子中。为了实现这些目标，我们将使用新颖的方法，通过分析有毒反应的分子生物学，将对信号转导途径的理解汇集在一起。这项工作的结果将进一步了解我们对二恶英引诱的生物学途径之间的串扰，这将确定对二恶英不同毒性作用至关重要的分子因素，并将有助于表征其预防的主要候选靶标。了解二恶英激活AHR激活的信号传导机制将立即提供大量信息，适用于研究二恶英是原型的400多种环境毒物和AH受体激动剂的毒性。