Aryl hydrocarbon receptor regulation of the cell cycle by chromatin modification

芳烃受体通过染色质修饰调节细胞周期

基本信息

批准号：
7625926
负责人：
REBEKA RAND MERSON
金额：
$ 10.8万
依托单位：
RHODE ISLAND COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2010-10-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7625926
关键词：
ARA9 protein Acetyltransferase Address Anthracenes Antibodies Apoptosis Aromatic Hydrocarbons Aromatic Polycyclic Hydrocarbons Aryl Hydrocarbon Receptor Basic Science Binding CDKN2A gene Carcinogens Cell Culture Techniques Cell Cycle Cell Cycle Arrest Cell Cycle Progression Cell Cycle Regulation Cell Cycle Stage Cell Proliferation Cell Proliferation Regulation Cells Chemicals Chromatin Complex CpG Islands Cyclin-Dependent Kinase Inhibitor 2A DNA DNA Methylation DNA Methyltransferase DNA Modification Methylases Dioxins E2F Transcription Factor 1 E2F transcription factors Embryo Environment Environmental Carcinogens Enzymes Epigenetic Process Exposure to Family Gene Expression Regulation Genes Genomics Growth HDAC1 gene Helper-Inducer T-Lymphocyte Histone Deacetylase Histones Human Human Genome In Vitro Knock-out Malignant Neoplasms Mammalian Cell Mitosis Modeling Molecular Nature Nuclear Protein Nuclear Proteins Phase Play Polychlorinated Biphenyls Principal Investigator Radiolabeled Receptor Activation Receptor Signaling Recombinant Proteins Recruitment Activity Regulation Regulator Genes Research Research Personnel Response Elements Retinoblastoma Role Sequence Analysis Signal Pathway Spottings Testing Therapeutic Intervention Toxic Environmental Substances Transcriptional Regulation Tumor Suppressor Genes Tumor Suppressor Proteins aryl hydrocarbon receptor ligand carcinogenesis cdc Genes chromatin immunoprecipitation chromatin modification dimethylbenzanthracene genome database human EP300 protein in vivo insight keratinocyte member novel programs promoter protein complex protein protein interaction radiotracer receptor receptor binding research study response tumor

项目摘要

DESCRIPTION (provided by applicant) Uncontrolled cell proliferation is the hallmark of cancer. Exposure to certain chemicals in the environment disrupts the regulation of cell proliferation, ultimately leading to carcinogenesis. The aryl hydrocarbon receptor (AhR) binds to numerous synthetic and natural compounds including environmental carcinogens such as some polyhalogenated aromatic hydrocarbons (e.g., dioxins, polychlorinated biphenyls) and polycyclic aromatic hydrocarbons (e.g., dimethylbenzanthracene). The AhR signaling pathway has been implicated in regulation and dysregulation of the cell cycle; however the molecular mechanisms of this regulatory role are unclear. Most of the previously described interactions have been established in asynchronously growing cell cultures. The overall hypothesis of the proposed research is that AhR is a cell cycle regulator and the role it plays, either as a promoter of cell cycle progression or an inducer of cell cycle arrest, depends on its ability to differentially associate with multi-protein complexes comprised of cell cycle regulators and chromatin modifiers. This research proposes to investigate the molecular mechanisms of chemically-induced carcinogenesis initiated through activation of the aryl hydrocarbon receptor signaling pathway in mammalian cell culture models amenable to synchronization by 1) determining protein-protein interactions with chromatin modifiers (histone deacetylases and DNA methyltransferases) and cell cycle regulators (E2F transcription factors, retinoblastoma [RB] tumor suppressors) at specific stages of the cell cycle, 2) assessing the targeting of cell cycle gene promoters by AhR-containing transcriptional complexes by chromatin immunoprecipitation (ChIP) experiments and genomic approaches including ChlP-on-chip and ChlP-cloning, and 3) determining how the regulatory role of AhR is disrupted by carcinogenic AhR ligands. The results from this research will provide a better understanding of chemically-induced carcinogenesis and gain insight into the molecular mechanisms for the varied responses in the cell cycle observed following exposure to environmental toxicants. Furthermore, the results will provide the basic research for developing therapeutic interventions to chemical-induced tumors and may predict cell cycle stages susceptible to cancer.

描述（由申请人提供）不受控制的细胞增殖是癌症的标志。在环境中暴露于某些化学物质会破坏细胞增殖的调节，最终导致致癌作用。芳基烃受体（AHR）与许多合成和天然化合物结合，包括环境致癌物，例如一些多面化的芳族烃（例如，二恶英，多氯化的二苯基）和多环芳烃和多碳酸盐芳族芳族芳族芳族氢碳（例如，二甲基苯基苯甲酰苯苯甲苯甲酸）。 AHR信号通路与细胞周期的调节和失调有关。但是，这种调节作用的分子机制尚不清楚。先前描述的大多数相互作用已在异步生长的细胞培养物中建立。提出的研究的总体假设是AHR是细胞周期调节剂及其扮演的作用，要么是细胞周期进展的启动子，要么是细胞周期停滞的诱导剂，取决于其与包含多蛋白质复合物差异化的能力细胞周期调节剂和染色质修饰符。这项研究建议研究通过激活芳基烃受体信号通路在哺乳动物细胞培养模型中通过激活芳基烃受体信号传导途径引发的分子机制，可通过1）确定蛋白质 - 蛋白质相互作用与蛋白质蛋白质相互作用，以确定蛋白质蛋白质的相互作用与染色质修饰剂（组蛋白脱乙酰基酶和DNA酶酶和DNA甲基甲基甲基甲基甲基甲基甲基甲基甲基甲基甲基甲基甲基酯））细胞周期调节剂（E2F转录因子，视网膜母细胞瘤[RB]抑制剂）在细胞周期的特定阶段，2）通过染色质免疫沉淀（CHIP）实验（包括基因组方法）评估细胞周期基因启动子的靶向。片上的CHLP和CHLP克隆，以及3）确定AHR的调节作用如何受到致癌AHR配体的破坏。这项研究的结果将更好地理解化学诱导的致癌作用，并深入了解暴露于环境有毒物质后观察到的细胞周期中各种反应的分子机制。此外，结果将为对化学诱导的肿瘤开发治疗干预措施提供基础研究，并可以预测易受癌症的细胞周期阶段。