Regulation of cyp1a1 by Ah Receptor and NFkB Interaction

Ah 受体和 NFkB 相互作用对 cyp1a1 的调节

• 批准号: 7099440
• 负责人: YANAN TIAN
• 金额: $ 27万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7099440
• 关键词: SDS polyacrylamide gel electrophoresis; aromatic hydrocarbon receptor; biological signal transduction; cytokine; dioxins; environmental toxicology; gene expression; gene induction /repression; histones; immunoprecipitation; lipopolysaccharides; methyltransferase; nuclear factor kappa beta; phosphorylation; polymerase chain reaction; protein protein interaction; transcription factor; yeast two hybrid system

DESCRIPTION (provided by applicant): Dioxin and related halogenated aromatic hydrocarbons are ubiquitous, persistent environmental contaminants causing adverse responses to human and wildlife. Most of the toxic responses induced by dioxin are mediated by the aryl hydrocarbon receptor (AhR). Therefore, central to our understanding of dioxin-induced toxicity is to elucidate the mechanism of the AhR-regulated gene expressions. In earlier studies, we have found a physical association and functional reciprocal repression between the AhR and NF-kB pathways (J. Biol. Chem. 274,510). Because NF-kB is a pleiotropic transcription factor involved in many physiological functions that are known to be adversely affected by dioxin, the AhR-mediated suppression of NF-kB offers a mechanism for some aspects of hitherto poorly understood dioxin-induced toxic responses, such as the immune suppression and abnormal skin proliferation. Reciprocally, suppression of AhR by NF-kB activation has also offered an underlying mechanism for the long-standing observation that inflammatory cytokines and lipopolysaccharide suppress AhR-regulated cytochrome P450 1A1/1A2 and decrease capacity of xenobiotic (including clinical drugs) metabolism (J. Biol. Chem. 276,39638). In recent studies, by using chromatin immunoprecipitation (CHIP) assay, we have obtained new results revealing that the AhR/NF-kB interaction converges at level of transcription involving (1) control of transcription elongation and (2) chromatin modifications. In AIM I of this proposal we will investigate a mechanism in which AhR/NF-kB interaction regulates cyp1a1 transcription elongation by directly interacting with p-TEFb (positive transcription elongation factor b), which plays a critical role in elongation control. In AIM II, we will investigate histone modifications (histone acetylation and methylation) in response to the diametrically opposing actions of AhR and NF-kB and to establish the residue-specific and combinatorial patterns of histone modifications (histone code) associated with "on and off" states of cyp1a1. We will also investigate a novel AhR interactive protein (identified by CytoTrap yeast two hybrid screening) SUV39H2 methyltransferase for its role in AhR-mediated gene silencing, which may be important for male imprinting. The proposed studies will help us gain mechanistic understandings of the functions of AhR and NF-kB in normal physiology as well as pathogenesis induced by dioxin and related compounds.

描述（由申请人提供）：二恶英和相关的卤代芳香烃是普遍存在的持久性环境污染物，会对人类和野生动物造成不良反应。二恶英引起的大多数毒性反应是由芳烃受体（AhR）介导的。因此，我们了解二恶英引起的毒性的核心是阐明 AhR 调节基因表达的机制。在早期的研究中，我们发现 AhR 和 NF-kB 通路之间存在物理关联和功能性相互抑制 (J. Biol. Chem. 274,510)。由于 NF-kB 是一种多效性转录因子，参与许多已知会受到二恶英不利影响的生理功能，因此 AhR 介导的 NF-kB 抑制为迄今为止知之甚少的二恶英诱导的毒性反应的某些方面提供了一种机制，例如由于免疫抑制和皮肤异常增生。相反，NF-kB 激活对 AhR 的抑制也为长期观察到的炎症细胞因子和脂多糖抑制 AhR 调节的细胞色素 P450 1A1/1A2 并降低异生物质（包括临床药物）代谢能力提供了潜在机制（J.化学。276，39638）。在最近的研究中，通过使用染色质免疫沉淀（CHIP）测定，我们获得了新的结​​果，揭示了 AhR/NF-kB 相互作用在转录水平上收敛，涉及（1）转录延伸的控制和（2）染色质修饰。在本提案的 AIM I 中，我们将研究 AhR/NF-kB 相互作用通过直接与 p-TEFb（正转录延伸因子 b）相互作用来调节 cyp1a1 转录延伸的机制，p-TEFb 在延伸控制中发挥着关键作用。在 AIM II 中，我们将研究组蛋白修饰（组蛋白乙酰化和甲基化）响应 AhR 和 NF-kB 截然相反的作用，并建立与“上和下”相关的组蛋白修饰（组蛋白代码）的残基特异性和组合模式。 cyp1a1 的“关闭”状态。我们还将研究一种新型 AhR 相互作用蛋白（通过 CytoTrap 酵母二杂交筛选鉴定）SUV39H2 甲基转移酶在 AhR 介导的基因沉默中的作用，这可能对雄性印记很重要。拟议的研究将帮助我们从机制上了解 AhR 和 NF-kB 在正常生理学中的功能以及二恶英和相关化合物诱导的发病机制。