Identification of Nrf2 DNA binding Co-Factors involved in regulation of gene expr

鉴定参与基因表达调节的 Nrf2 DNA 结合辅因子

• 批准号: 8194000
• 负责人: Christine Happel
• 金额: $ 2万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-20 至 2012-02-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8194000
• 关键词: A549; Antioxidants; Binding; Biological Assay; Biological Models; Cancer Cell Growth; Cells; Chemicals; Co-Immunoprecipitations; Complex; DNA Binding; DNA-Protein Interaction; Data; Drug Metabolic Detoxication; Enzymes; Event; Gene Expression; Gene Expression Profiling; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genetic Transcription; Health; Immunoprecipitation; Intervention; Lung Neoplasms; Malignant neoplasm of lung; Mass Spectrum Analysis; Mediating; Messenger RNA; Microarray Analysis; Mutation; NF-E2-related factor 2; Non-Small-Cell Lung Carcinoma; Nuclear Translocation; Oxidation-Reduction; Phase; Play; Process; Proteins; Regulation; Regulatory Element; Reporter; Reporting; Repression; Resistance; Response Elements; Role; Small Interfering RNA; Stress; Systems Biology; Testing; Therapeutic; Therapeutic Intervention; Tissue-Specific Gene Expression; Transcriptional Activation; Ubiquitination; base; cancer cell; carcinogenesis; chemotherapy; crosslink; dimer; in vivo; inhibitor/antagonist; insight; knock-down; liquid chromatography mass spectrometry; new therapeutic target; novel; nuclear factor-erythroid 2; overexpression; programs; promoter; protein complex; response; transcription factor; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Nuclear factor erythroid-2 related factor-2 (Nrf2) is a redox-sensitive transcription factor that regulates genes encoding phase II detoxification enzymes and antioxidant proteins. Following oxidative or electrophilic stress, Nrf2 is liberated from its inhibitor, Keap1, allowing nuclear translocation, and the transcriptional induction of its target genes. Nrf2 plays a central role in the regulation of antioxidant response element (ARE)-mediated gene expression. Our lab has reported that genetic alterations in Keap1 are a frequent occurrence in non-small-cell lung cancer (NSCLC) that leads to increased Nrf2 expression and constitutive activation of Nrf2-mediated gene expression. Constitutive activation of Nrf2 due to the loss of Keap1 function in lung tumors contributes to the survival and growth of cancer cells as well as confers chemoresistance in NSCLC. The identification of a well-defined Nrf2 regulatory program is a critical step in understanding the dysregulation of Nrf2 activity in cancer cells, which promotes both tumorigenesis and therapeutic resistance leading to novel intervention strategies. Our preliminary data from microarray analysis demonstrate that constitutive activation of Nrf2 in lung cancer cells up-regulates a large number of genes with overarching implications in tumorigenesis and chemoresistance. Recent studies provide strong evidence that DNA binding co- factors can modulate Nrf2-driven transcriptional activity and target gene expression. This proposal outlines a systems biology approach for the identification of binding partners in the Nrf2 transcriptional activation complex that are responsible for the differential regulation of Nrf2 target gene expression in lung cancer. These studies will reveal the role of Nrf2 binding partners in ARE- directed gene expression. By understanding the regulation of Nrf2-mediated transcription, we will discover the mechanism responsible for the altered gene expression in lung cancer. This proposal aims to identify novel therapeutic targets involved in the regulation of Nrf2-mediated gene expression and gain insight into the role of Nrf2-mediated gene expression in carcinogenesis and chemotherapeutic resistance.

描述（由申请人提供）：核因子erythroid-2相关因子2（Nrf2）是一种氧化还原敏感转录因子，调节编码II相解毒酶和抗氧化蛋白的基因。在氧化或亲电应激后，Nrf2 从其抑制剂 Keap1 中释放出来，从而实现核易位及其靶基因的转录诱导。 Nrf2 在抗氧化反应元件 (ARE) 介导的基因表达调节中发挥核心作用。我们的实验室报告称，Keap1 的基因改变在非小细胞肺癌 (NSCLC) 中经常发生，导致 Nrf2 表达增加以及 Nrf2 介导的基因表达的组成型激活。肺肿瘤中 Keap1 功能丧失导致 Nrf2 的组成性激活有助于癌细胞的存活和生长，并赋予 NSCLC 化疗耐药性。确定明确的 Nrf2 调控程序是了解癌细胞中 Nrf2 活性失调的关键一步，这种失调会促进肿瘤发生和治疗耐药，从而产生新的干预策略。我们来自微阵列分析的初步数据表明，肺癌细胞中 Nrf2 的组成型激活上调大量基因，对肿瘤发生和化疗耐药具有总体影响。最近的研究提供了强有力的证据，表明 DNA 结合辅因子可以调节 Nrf2 驱动的转录活性和靶基因表达。该提案概述了一种系统生物学方法，用于鉴定 Nrf2 转录激活复合物中的结合伴侣，这些结合伴侣负责肺癌中 Nrf2 靶基因表达的差异调节。这些研究将揭示 Nrf2 结合伴侣在 ARE 定向基因表达中的作用。通过了解 Nrf2 介导的转录调控，我们将发现肺癌基因表达改变的机制。该提案旨在确定参与 Nrf2 介导的基因表达调节的新治疗靶点，并深入了解 Nrf2 介导的基因表达在癌发生和化疗耐药中的作用。