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

描述(申请人提供)：核因子红系2相关因子-2(NRF2)是一种氧化还原敏感的转录因子，调节编码II期解毒酶和抗氧化蛋白的基因。在氧化或亲电应激后，Nrf2从其抑制物Keap1中释放出来，允许核转位，并对其目标基因进行转录诱导。Nrf2在抗氧化剂反应元件(ARE)介导的基因表达调控中起着核心作用。我们的实验室已经报道，Keap1的基因改变在非小细胞肺癌(NSCLC)中经常发生，导致Nrf2表达增加和Nrf2介导的基因表达的结构性激活。肺癌中Keap1功能丧失导致Nrf2的结构性激活，有助于癌细胞的存活和生长，并在非小细胞肺癌中产生化疗耐药。明确的Nrf2调控程序的确定是理解癌细胞中Nrf2活性失调的关键一步，Nrf2活性的失调促进了肿瘤的发生和治疗耐药，导致了新的干预策略。我们来自微阵列分析的初步数据表明，肺癌细胞中Nrf2的结构性激活上调了大量基因，这些基因在肿瘤发生和化疗耐药中具有重要意义。最近的研究提供了强有力的证据表明，DNA结合辅助因子可以调节Nrf2驱动的转录活性和靶基因的表达。本提案概述了一种系统生物学方法，用于鉴定Nrf2转录激活复合体中的结合伙伴，这些结合伙伴负责肺癌中Nrf2靶基因表达的差异调控。这些研究将揭示Nrf2结合伙伴在ARE导向的基因表达中的作用。通过了解Nrf2介导的转录调控，我们将发现肺癌中基因表达变化的机制。本研究旨在寻找参与调控Nrf2介导的基因表达的新的治疗靶点，并深入了解Nrf2介导的基因表达在肿瘤发生和化疗耐药中的作用。

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.