Role of Nrf2 Cross-Talk in Cancer Chemoprevention

描述(申请人提供)：Keap1-Nrf2信号通路的激活是对环境和内源性压力的适应性反应，用于使动物对化学致癌和其他形式的毒性具有抵抗力，而该通路的破坏则加剧了这些结果。该途径可被用于化学预防的巯基反应、小分子药理学和食品基试剂激活，调节一系列延长的细胞保护基因的诱导表达，通常是通过将转录因子Nrf2直接结合到靶基因启动子区域的抗氧化反应元件来实现的。然而，我们最近的工作表明，一些保护作用可能是通过与影响细胞存活和其他方面的细胞命运的其他途径的串扰间接介导的。这些相互作用通过：(I)通过诱导抗氧化、抗炎和致癌物解毒基因来预防大分子损伤；(Ii)诱导大分子损伤识别、修复/移除系统；以及(Iii)激活组织修复/再生途径，从而提供对化学胁迫的多层次、综合的反应。在这个项目中，我们试图使用分子、遗传和化学方法来检验这一假设，即Nrf2介导的化学保护既反映了其直接靶基因的激活，也反映了与其他影响细胞命运的适应性反应信号网络的相互作用，例如Notch1。拟议研究的总体目标有两个：评估通路串扰的潜在机制和后果，以及评估慢性诱导NRF2反应的功能意义和可能的不良影响，以促进安全、有效的化学预防药物的发现和使用。

DESCRIPTION (provided by applicant): Activation of the Keap1-Nrf2 signaling pathway is an adaptive response to environmental and endogenous stresses and serves to render animals resistant to chemical carcinogenesis and other forms of toxicity, whereas disruption of the pathway exacerbates these outcomes. This pathway, which can be activated by sulfhydryl reactive, small-molecule pharmacologic and food-based agents used in chemoprevention, regulates the inducible expression of an extended battery of cytoprotective genes, often by direct binding of the transcription factor Nrf2 to antioxidant response elements in the promoter regions of target genes. However, our recent work indicates that some of the protective effects may be mediated indirectly through cross-talk with additional pathways affecting cell survival and other aspects of cell fate. These interactions provide a multi-tiered, integrated response to chemical stresses through: (i) prevention of macromolecular damage through induction of antioxidative, anti-inflammatory and carcinogen detoxication genes; (ii) induction of macromolecular damage recognition, repair/removal systems; and (iii) activation of tissue repair/regeneration pathways. In this project we seek to use molecular, genetic and chemical approaches to test the hypothesis that chemoprotection mediated by Nrf2 reflects both activation of its direct target genes but importantly cross- talk with other adaptive response signaling networks affecting cell fate, such as Notch1. The overall goals of the proposed studies are two-fold: to assess the underlying mechanisms and consequences of pathway cross-talk and to assess the functional significance and possible untoward effects of chronic induction of the Nrf2 response in order to facilitate the identification and utilization of safe, efficacious chemopreventive agents.