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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：
7096124
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 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7096124
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 Cycle Cell Cycle Arrest Cell Cycle Progression Cell Cycle Regulation Cell Cycle Stage Cell Proliferation Cell Proliferation Regulation Cells Chemicals Chromatin Complex CpG Islands Cultured Cells 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 In Vitro Knock-out Malignant Neoplasms Mammalian Cell Mitosis Modeling Modification Molecular Nature Nuclear Protein Nuclear Proteins Phase Play Polychlorinated Biphenyls Polymerase Chain Reaction Principal Investigator Proteins Radiolabeled Rate 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 anthracene aryl hydrocarbon receptor ligand carcinogenesis cdc Genes chromatin immunoprecipitation dimethylbenzanthracene genome database human EP300 protein in vivo insight keratinocyte member novel programs promoter 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。暴露于环境中的某些化学物质会破坏细胞增殖的调节，最终导致致癌。芳烃受体（AhR）与许多合成和天然化合物结合，包括环境致癌物，例如一些多卤代芳烃（例如，二恶英、多氯联苯）和多环芳烃（例如，二甲基苯并蒽）。AhR信号通路与细胞周期的调节和失调有关，但其调节作用的分子机制尚不清楚。大多数先前描述的相互作用已经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是一种细胞周期调节剂，它所起的作用，无论是作为细胞周期进程的促进剂还是细胞周期阻滞的诱导剂，都取决于它与由细胞周期调节剂和染色质修饰剂组成的多蛋白复合物差异相关的能力。本研究拟在哺乳动物细胞培养模型中，通过1）确定与染色质修饰剂的蛋白质-蛋白质相互作用，（组蛋白脱乙酰酶和DNA甲基转移酶）和细胞周期调节剂（E2 F转录因子、视网膜母细胞瘤[RB]肿瘤抑制因子）在细胞周期的特定阶段，2）通过染色质免疫沉淀（ChIP）评估含有AhR的转录复合物对细胞周期基因启动子的靶向作用实验和基因组方法，包括ChIP芯片和ChIP克隆，和3）确定致癌AhR配体如何破坏AhR的调节作用。这项研究的结果将提供更好的理解化学诱导的致癌作用，并深入了解暴露于环境毒物后观察到的细胞周期中不同反应的分子机制。此外，这些结果将为开发化学诱导肿瘤的治疗干预措施提供基础研究，并可能预测易患癌症的细胞周期阶段。