Ah Receptor Anatomy: Implications for Dioxin Toxicity

Ah 受体解剖：对二恶英毒性的影响

• 批准号: 6383979
• 负责人: Cornelis Johan Elferink
• 金额: $ 25.49万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-03-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6383979
• 关键词: DNA binding protein; aromatic hydrocarbon receptor; carbopolycyclic compound; cell growth regulation; complementary DNA; dioxins; environmental toxicology; gel mobility shift assay; immunocytochemistry; immunoprecipitation; laboratory rabbit; laboratory rat; liver regeneration; molecular cloning; polymerase chain reaction; protein protein interaction; protein sequence; protein structure function; receptor binding; receptor expression; retinoblastoma protein; toxicant interaction; toxin metabolism; western blottings

DESCRIPTION (provided by applicant): Toxin and virus induced liver injury resulting in the loss of hepatic tissue, triggers a regenerative response o restore liver cell mass. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor functionally identified with proliferative processes. The AhR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is he prototype for a class of compounds responsible for a range of toxic or adaptive endpoints. The underlying mechanism responsible for TCDD toxicity remains poorly defined, but appears to reflect disruptions in normal cell proliferation and differentiation. Our long-term goal is to understand mechanistically how the AhR contributes to liver homeostasis by regulating cell proliferation, and to identify the molecular basis for TCDD toxicity. We have identified a component critical for AhR function: the Retinoblastoma tumor suppressor protein (pRb). Our evidence suggests that pRb may be a coactivator in AhR signaling during TCDD induced G1 phase cell cycle arrest in cultured liver cells. We hypothesize that the AhR plays an important role in liver homeostasis, in part by regulating cell proliferation via a process dependent on the AhR-pRb interaction. The goal of this proposal is to functionally characterize the AhR-pRb interaction, and to examine the AhR's role in liver regeneration in vivo. Aim 1 will determine whether TCDD induced cell cycle arrest requires a transcriptionally competent A1IR complex comprising the AhR/Arnt protein dimer, by testing the effect of targeted mutations on AhR mediated G1 arrest. Aim 2 will functionally characterize the AhR-pRb interaction. Studies will examine the importance of AhR coactivation by pRb and related proteins, the precise nature of the AhR-pRb interaction, and the effect of pRb phosphorylation on AhR activity. Aim 3 will examine how the AhR contributes to cell cycle control in vivo during liver regeneration induced by partial hepatectomy. Studies will investigate the effects of TCDD and AhR mutations using adenovirus-mediated gene transfer, on in vivo liver regeneration in AhR, p27Kipl and p21Cip1 nullizygous mice, and the congenic wild-type mice.

描述（由申请方提供）：毒素和病毒诱导的肝损伤 导致肝组织的损失，引发再生反应， 恢复肝细胞质量。芳香烃受体（AhR）是一种 配体激活的转录因子，功能鉴定为 增殖过程。AhR配体2，3，7，8-四氯二苯并对二恶英 （TCDD）是一类化合物的原型，负责一系列 毒性或适应性终点。TCDD的基本机制 毒性仍然不清楚，但似乎反映了正常的破坏， 细胞增殖和分化。我们的长期目标是了解 AhR如何通过调节细胞内环境来促进肝脏稳态 增殖，并确定TCDD毒性的分子基础。我们有 确定了AhR功能的关键成分：视网膜母细胞瘤肿瘤 抑制蛋白（pRb）。我们的证据表明pRb可能是一种共激活剂 在TCDD诱导的细胞周期G1期阻滞过程中AhR信号的变化 肝细胞我们推测AhR在肝脏中起着重要的作用， 体内平衡，部分通过调节细胞增殖，通过依赖于细胞增殖的过程， 关于AhR-pRb相互作用。本提案的目标是在功能上 表征AhR-pRb相互作用，并检查AhR在肝脏中的作用 体内再生目的1：探讨TCDD是否诱导细胞周期的变化 阻滞需要转录活性的A1 IR复合物，其包含 AhR/Arnt蛋白二聚体，通过测试靶向突变对AhR的影响 介导的G1期阻滞。目的2将功能性地表征AhR-pRb 互动研究将检查pRb和pRb共同激活AhR的重要性， 相关蛋白质，AhR-pRb相互作用的确切性质，以及 pRb磷酸化对AhR活性的影响目标3将研究AhR如何 在肝再生诱导过程中有助于体内细胞周期控制， 肝部分切除术研究将调查TCDD和AhR的影响 使用腺病毒介导的基因转移在体内肝脏上进行突变 在AhR、p27 Kipl和p21 Cipl缺失小鼠中， 野生型小鼠。