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

描述（由申请人提供）：核因子红细胞-2相关因子-2（Nrf 2）是一种氧化还原敏感性转录因子，可调节编码II期解毒酶和抗氧化蛋白的基因。氧化或亲电应激后，Nrf 2从其抑制剂Keap 1中释放出来，允许核转位及其靶基因的转录诱导。Nrf 2在抗氧化反应元件（ARE）介导的基因表达调控中起着重要作用。我们的实验室已经报道，Keap 1的遗传改变在非小细胞肺癌（NSCLC）中经常发生，导致Nrf 2表达增加和Nrf 2介导的基因表达的组成性激活。由于肺肿瘤中Keap 1功能丧失而导致的Nrf 2组成性激活有助于癌细胞的生存和生长，并赋予非小细胞肺癌化疗耐药性。确定一个明确的Nrf 2调控程序是理解癌细胞中Nrf 2活性失调的关键一步，Nrf 2活性失调促进肿瘤发生和治疗耐药性，从而导致新的干预策略。我们从微阵列分析的初步数据表明，在肺癌细胞中的Nrf 2的组成性激活上调了大量的基因，在肿瘤发生和化疗耐药性的总体影响。最近的研究提供了强有力的证据，DNA结合辅因子可以调节Nrf 2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，用于识别Nrf 2转录激活复合物中负责肺癌中Nrf 2靶基因表达差异调节的结合伴侣。这些研究将揭示Nrf 2结合伴侣在ARE指导的基因表达中的作用。通过了解Nrf 2介导的转录调控，我们将发现肺癌中基因表达改变的机制。该提案旨在确定参与调节Nrf 2介导的基因表达的新的治疗靶点，并深入了解Nrf 2介导的基因表达在致癌和化疗耐药性中的作用。

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.