Reddy Narsa M, Kleeberger Steven R, Yamamoto Masayuki, Kensler Thomas W, Scollick Catherine, Biswal Shyam, Reddy Sekhar P
Department of Environmental Health Sciences, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
Physiol Genomics. 2007 Dec 19;32(1):74-81. doi: 10.1152/physiolgenomics.00126.2007. Epub 2007 Sep 25.
The beta zipper (bZip) transcription factor, nuclear factor erythroid 2, like 2 (Nrf2), acting via an antioxidant/electrophile response element, regulates the expression of several antioxidant enzymes and maintains cellular redox homeostasis. Nrf2 deficiency diminishes pulmonary expression of several antioxidant enzymes, rendering them highly susceptible to various mouse models of prooxidant-induced lung injury. We recently demonstrated that Nrf2 deficiency impairs primary cultured pulmonary epithelial cell proliferation and greatly enhances sensitivity to prooxidant-induced cell death. Glutathione (GSH) supplementation rescued cells from these defects associated with Nrf2 deficiency. To further delineate the mechanisms by which Nrf2, via redox signaling, regulates cellular protection and proliferation, we compared the global expression profiling of Nrf2-deficient cells with and without GSH supplementation. We found that GSH regulates the expression of various networks of transcriptional programs including 1) several antioxidant enzymes involved in cellular detoxification of reactive oxygen species and recycling of thiol status and 2) several growth factors, growth factor receptors, and integrins that are critical for cell growth and proliferation. We also found that Nrf2 deficiency enhances the expression levels of several genes encoding proinflammatory cytokines; however, GSH supplementation markedly suppressed their expression. Collectively, these findings uncover an important insight into the nature of genes regulated by Nrf2-dependent redox signaling through GSH that are involved in cellular detoxification and proliferation.
β拉链（bZip）转录因子，即核因子红细胞2样2（Nrf2），通过抗氧化/亲电反应元件发挥作用，调节多种抗氧化酶的表达并维持细胞氧化还原稳态。Nrf2缺乏会降低多种抗氧化酶在肺部的表达，使其对多种促氧化剂诱导的肺损伤小鼠模型高度敏感。我们最近证明，Nrf2缺乏会损害原代培养的肺上皮细胞增殖，并大大增强对促氧化剂诱导的细胞死亡的敏感性。补充谷胱甘肽（GSH）可使细胞免受与Nrf2缺乏相关的这些缺陷的影响。为了进一步阐明Nrf2通过氧化还原信号调节细胞保护和增殖的机制，我们比较了补充和不补充GSH的Nrf2缺陷细胞的整体表达谱。我们发现，GSH调节各种转录程序网络的表达，包括1）参与活性氧细胞解毒和硫醇状态循环的几种抗氧化酶，以及2）对细胞生长和增殖至关重要的几种生长因子、生长因子受体和整合素。我们还发现，Nrf2缺乏会增加几种编码促炎细胞因子的基因的表达水平；然而，补充GSH可显著抑制它们的表达。总的来说，这些发现揭示了对由Nrf2依赖的氧化还原信号通过GSH调节的、参与细胞解毒和增殖的基因性质的重要见解。
