Regulation of NEMO modifications in radiation-induced NF-kB signaling

辐射诱导的 NF-kB 信号传导中 NEMO 修饰的调节

• 批准号: 8656285
• 负责人: SHIGEKI MIYAMOTO
• 金额: $ 2.86万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8656285
• 关键词: Address; Antineoplastic Agents; Apical; Apoptotic; Attenuated; Binding; C-terminal; Camptothecin; Cancer Patient; Cell Death; Cell Nucleus; Cell Survival; Cells; Cessation of life; Complex; Couples; DNA Damage; DNA Double Strand Break; Data; Death Domain; Doxorubicin; Drug Targeting; Etoposide; Evaluation; Event; Genes; Germ-Line Mutation; Goals; Human; Immunologic Receptors; Ionizing radiation; Ligase; Malignant Neoplasms; Maps; Mediating; Methods; Modification; Molecular; Mus; Mutagens; NF-kappa B; NFKB Signaling Pathway; Nuclear; Pathway interactions; Peptide Hydrolases; Pharmaceutical Preparations; Phosphotransferases; Physiological; Play; Post-Translational Protein Processing; Publishing; Radiation; Radiation Tolerance; Radio; Regulation; Research; Resistance; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Site; Small Ubiquitin-Related Modifier Proteins; Specificity; Stimulus; Testing; Tissues; Ubiquitin; VP 16; Whole-Body Irradiation; Zinc Fingers; ataxia telangiectasia mutated protein; base; cancer cell; cancer therapy; cell behavior; cytokine; enzyme mechanism; improved; in vivo; killings; mouse model; novel; paralogous gene; protein inhibitors of activated STAT; response; transcription factor

Activation of NF-kB by DNA-damaging anticancer agents, including ionizing radiation (IR), has emerged as an important modulator of malignant cell behaviors, such as resistance to apoptotic cell death. This signal transduction pathway also serves as a paradigm to understand how nuclear DNA damage may induce nucleus-to-cytoplasmic signal transduction pathways. We have previously discovered a novel nucleus-to-cytoplasmic NF-kB signaling pathway induced by IR and other agents that can induce DNA double strand breaks (DSBs). This signaling pathway involves a post-translational modification (PTM) of NEMO (NF-kB essential modulator)/IKK3, the regulatory subunit of the I:B kinase (IKK) complex, by SUMO-1 (small ubiquitin-like modifier 1). We now generated a novel Nemo[DK] knockin mice harboring a germ-line mutation of the sumoylation sites. In the current proposal, we will establish the physiological importance of this new NF-kB signaling pathway in response to IR by directly evaluating the role of NEMO sumoylation in vivo and further dissect the critical upstream and downstream mechanisms. The following three aims will address our central hypothesis that NEMO sumoylation plays a critical physiological role in mediating NF-kB activation by IR to modulate radiation sensitivity in vivo: Aim 1: Determine the roles of NEMO sumoylation in modulating radiation sensitivity in vivo. Aim 2: Reveal the upstream role of NEMO zinc finger in promoting NEMO sumoylation. Aim 3. Elucidate SUMO-1 specific downstream regulation of NEMO function. We believe that the proposed research is important for two major reasons. First, the described research will uncover novel NF-kB signal transduction mechanisms in response to DNA damage stimuli. Second, understanding the mechanisms of NF-kB activation by DNA damaging agents may help identify novel drug targets to improve the current methods of cancer therapy.

核因子-kB被DNA损伤的抗癌剂激活，包括电离辐射(IR)，已成为抵抗细胞凋亡等恶性细胞行为的重要调节剂。这一信号转导途径也是理解核DNA损伤如何诱导核-细胞质信号转导途径的范例。我们以前发现了一种新的核质-核转录因子-kB信号通路，它可以诱导DNA双链断裂(DSB)。该信号通路涉及I：B激酶(IKK)复合体的调节亚基NEMO(核因子-kB必需调节物)/IKK3被SUMO-1(小泛素样修饰物1)翻译后修饰。我们现在创造了一种新的Nemo[DK]敲门小鼠，该小鼠含有苏甲基化位点的胚系突变。在目前的方案中，我们将通过直接评估NEMO相扑在体内的作用来确定这一新的NF-kB信号通路在IR反应中的生理重要性，并进一步剖析关键的上游和下游机制。以下三个目标将解决我们的核心假设，即Nemo相扑在IR介导的NF-kB激活中发挥关键的生理作用，从而调节体内的辐射敏感性：目的1：确定Nemo相扑在体内调节辐射敏感性中的作用。目的2：揭示NEMO锌指在促进NEMO相扑甲基化中的上游作用。目的3.阐明SUMO-1对NEMO功能的特异性下游调控。我们认为，拟议的研究之所以重要，主要有两个原因。首先，所描述的研究将揭示响应DNA损伤刺激的新的核因子-kB信号转导机制。其次，了解DNA损伤剂激活核因子-kB的机制可能有助于识别新的药物靶点，以改进目前的癌症治疗方法。