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The role of IkappaB kinase beta in redox modulation.

机译：IkappaB激酶β在氧化还原调节中的作用。

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摘要

The IkappaB kinase beta (IKKbeta) is a critical component of the classical inflammatory signaling pathway that activates nuclear factor kappaB (NF-kappaB) and propagates inflammatory responses. Recent genetic studies in mice suggest that IKKbeta also has physiological roles in the prevention of oxidative stress. The central hypothesis of this thesis is that the IKKbeta-NF-kappaB signal transduction pathway is crucial for maintaining redox homeostasis and preventing excessive reactive oxygen species (ROS). We test this hypothesis by addressing the following pertinent questions.;1. Does the IKKbeta-NF-kappaB pathway regulate redox homeostasis? Redox homeostasis is largely maintained by a group of antioxidant enzymes and small scavenging molecules, such as reduced glutathione (GSH) and metallothionein (MT). Our results show that genetic and pharmacological inactivation of the IKKbeta-NF-kappaB pathway reduces the cellular GSH and MT1 levels.;2. What are the consequences of IKKbeta inactivation? We show that the IKKbeta-NF-kappaB pathway is required for protection against oxidative injury caused by a wide variety of oxidative stress inducers, including environmental toxic compounds, such as arsenic, and therapeutic anti-cancer drugs, such as cisplatin and taxol. Under stress conditions, cells deficient in IKKbeta display a marked increase in ROS accumulation, which leads to activation of the MKK4-c-JUN N-terminal kinase (JNK) pathway, c-JUN phosphorylation and apoptosis. Hence, the IKKbeta-NF-kappaB pathway maintains ROS scavenging capacity and serves as a critical biological checkpoint for cell fate determination in stress environment.;3. What are the mechanisms for the IKKbeta-NF-kappaB pathway in GSH regulation? It has long been established that GSH is an important defense against the toxicity of oxidants, of which exposure is an everyday occurrence. Our results show that at least two mechanisms are involved in GSH regulation by IKKbeta. First, IKKbeta is needed for the optimal activities of the transcription factors NF-kappaB and aryl hydrocarbon receptor (AHR), which coordinately activate the expression of genes encoding the catalytic (GCLC) and modifier (GCLM) subunits of glutathione-cysteine ligase (GCL). Because GCL is the rate limiting enzyme for GSH biosynthesis, its reduced expression in the IKKbeta inactive cells leads to severe GSH deficiency. Second, IKKbeta acts as a suppressor of the transforming growth factor beta (TGFbeta) pathway preventing TGFbeta induced GSH depletion.;4. What is the implication of the IKKbeta-NF-kappaB pathway in diseases? Many environmental toxic agents, such as arsenic, exert deleterious effects by directly or indirectly altering the cellular redox status. Activation of the IKKbeta-NF-kappaB pathway, essentially required for maintaining redox capacity, may be useful for developing preventive antidotes for environmental toxicants. On the other hand, a relatively high NF-kappaB activity in cancer cells may lead to high GSH, thereby conferring resistance to chemotherapy. Therefore, inactivation of the IKKbeta-NF-kappaB pathway may potentiate the efficacy of oxidative stress-based anti-cancer therapy. Furthermore, modulation of IKKbeta could affect other signaling networks. Studies presented in this thesis describe comprehensive crosstalk of IKKbeta with the TGFbeta and JNK pathways. Such crosstalk may constitute a decision-making process that determines the cell fate that needs to be addressed in the context of specific biological settings
机译：IkappaB激酶beta（IKKbeta）是经典的炎症信号通路的关键组成部分，它激活核因子kappaB（NF-kappaB）并传播炎症反应。最近对小鼠的遗传研究表明，IKKbeta在预防氧化应激方面也具有生理作用。本论文的主要假设是，IKKbeta-NF-kappaB信号转导通路对于维持氧化还原稳态和防止过多的活性氧（ROS）至关重要。我们通过解决以下相关问题来检验该假设：1。 IKKbeta-NF-kappaB途径是否调节氧化还原稳态？氧化还原稳态主要由一组抗氧化酶和小的清除分子（例如还原型谷胱甘肽（GSH）和金属硫蛋白（MT））维持。我们的结果表明，IKKbeta-NF-kappaB途径的遗传和药理失活降低了细胞GSH和MT1的水平。 IKKbeta失活的后果是什么？我们表明，IKKbeta-NF-kappaB通路是保护免受各种氧化应激诱导物（包括环境毒性化合物，如砷）和治疗性抗癌药物（如顺铂和紫杉醇）引起的氧化损伤所必需的。在应激条件下，缺乏IKKbeta的细胞在ROS积累上显示出明显的增加，从而导致MKK4-c-JUN N端激酶（JNK）途径的激活，c-JUN磷酸化和细胞凋亡。因此，IKKbeta-NF-kappaB通路保持了ROS清除能力，并作为确定应激环境下细胞命运的关键生物学检查点。3。在GSH调节中IKKbeta-NF-kappaB途径的机制是什么？长期以来，人们已经确定，谷胱甘肽是抵抗氧化剂毒性的重要防御剂，氧化剂的暴露每天都在发生。我们的结果表明，至少两种机制参与了IKKbeta对GSH的调控。首先，IKKbeta对于转录因子NF-κB和芳烃受体（AHR）的最佳活性是必需的，它们可以协同激活编码谷胱甘肽-半胱氨酸连接酶（GCL）催化（GCLC）和修饰子（GCLM）亚基的基因的表达）。由于GCL是GSH生物合成的限速酶，因此它在IKKbeta非活性细胞中的表达降低会导致严重的GSH缺乏。其次，IKKbeta充当转化生长因子beta（TGFbeta）途径的抑制剂，阻止TGFbeta诱导的GSH消耗。4。 IKKbeta-NF-kappaB途径在疾病中的意义是什么？许多环境毒性剂，例如砷，通过直接或间接改变细胞氧化还原状态而发挥有害作用。维持氧化还原能力所必需的IKKbeta-NF-kappaB途径的激活可能对开发预防环境毒物的解毒剂很有用。另一方面，癌细胞中较高的NF-κB活性可能导致高GSH，从而赋予对化学疗法的抗性。因此，IKKbeta-NF-kappaB途径的失活可能增强基于氧化应激的抗癌治疗的功效。此外，IKKbeta的调制可能会影响其他信令网络。本文提出的研究描述了IKKbeta与TGFbeta和JNK途径的全面串扰。这种串扰可能会构成一个决策过程，该过程确定在特定生物学环境下需要解决的细胞命运

著录项

  • 作者

    Peng, Zhimin.;

  • 作者单位

    University of Cincinnati.;

  • 授予单位 University of Cincinnati.;
  • 学科 Health Sciences Toxicology.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 150 p.
  • 总页数 150
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 毒物学（毒理学）;
  • 关键词

  • 入库时间 2022-08-17 11:38:24

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