Genotoxic NF-kB Signaling in Cancer

癌症中的基因毒性 NF-kB 信号转导

• 批准号: 8403715
• 负责人: Zhaohui Wu
• 金额: $ 28.87万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8403715
• 关键词: Ablation; Adverse effects; Apoptosis; Applications Grants; Biological; Biological Process; Cancer Patient; Cancer Relapse; Cell Death; Cell Survival; Cessation of life; Complex; DNA Damage; Data; Disease; Genetic; Genotoxic Stress; Glutamates; Goals; Human; Immune response; Ionizing radiation; Knowledge; Lead; Leucine; Link; Lysine; Malignant Neoplasms; Mediating; Molecular; Mus; Mutagens; NF-kappa B; Nuclear; Nuclear Export; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Physiological; Play; Post-Translational Protein Processing; Process; Proteins; Radiation; Radio; Research; Resistance; Role; Serine; Signal Pathway; Signal Transduction; Site; Stimulus; Testing; Therapeutic; Therapeutic Agents; Treatment Efficacy; Ubiquitination; Whole-Body Irradiation; ataxia telangiectasia mutated protein; cancer cell; cancer genetics; cancer recurrence; cancer therapy; chemotherapy; drug sensitivity; improved; in vivo; inhibitor/antagonist; insight; irradiation; mortality; neoplastic cell; novel; novel strategies; public health relevance; response; small hairpin RNA; therapeutic development; transcription factor; tumor; ubiquitin ligase

DESCRIPTION (provided by applicant): The transcription factor nuclear factor kappaB (NF-kappaB) has been linked to acquired therapeutic resistance in multiple types of human cancer by inhibiting cell death and drug sensitivity of malignant cells. Various genotoxic agents used in cancer treatment, such as chemotherapeutic drugs and irradiation, have been shown to activate NF-kappaB, which is a major impediment to effective cancer treatment. Our long term goal is to improve efficacy of radio/chemotherapy and reduce the resistance of cancer cells by modulating the genotoxic NF-kappaB signaling pathway. Our previous studies established a conserved nuclear-to-cytoplasmic signaling pathway which orchestrates NF-kappaB activation induced by a broad range of genotoxic therapeutic agents. We found ELKS (a protein rich in glutamate, leucine, lysine and serine) is indispensable for the activation of IKK complex and NF-kappaB by genotoxic agents. Our preliminary studies indicate posttranslational modifications of ELKS, such as ubiquitination and phosphorylation, orchestrate the process of ATM-dependent IKK activation, resulting in NF-kappaB activation in response to genotoxic therapeutic agents. Genetic ablation of ELKS significantly increases the mortality in mice exposed to ionized radiation. We hypothesize that DNA damage-induced ELKS posttranslational modifications play critical roles in genotoxic NF-kappaB signaling pathway, and modulating genotoxic NF-kappaB activation may sensitize tumor cells to genotoxic agent-induced cell death. We will test the hypothesis with the following specific aims: Aim 1 is to characterize the ubiquitination of ELKS in genotoxic NF-kappaB signaling pathway. In aim 2, we will delineate how ATM regulates ELKS ubiquitination induced by genotoxic stress. We will further determine biological functions of ELKS mediated DNA damage response and its impact on therapeutic resistance in vivo in Aim3. Completion of the proposed specific aims outlined in this grant proposal will advance our understanding of the molecular mechanism governing the ELKS-mediated genotoxic NF- kappaB signaling and its function in regulating therapeutic resistance. Furthermore, the exploration of the non-neuronal function of ELKS and potential cytoplasmic activity of ATM may reveal novel research paradigm which may greatly broaden our knowledge in the physiological and pathological functions of these important molecules. We envision the selective inhibition of NF-kappaB activity by targeting specific signaling mechanisms will effectively alleviate the therapeutic resistance while keeping immune response intact in cancer patients.

描述（由申请人提供）： 转录因子核因子kappab（NF-kappab）通过抑制恶性细胞的细胞死亡和药物敏感性，与多种类型的人类癌症中获得的治疗性抗性有关。癌症治疗中使用的各种遗传毒性剂，例如化学治疗药物和辐照，已显示出激活NF-kappab，这是对有效癌症治疗的主要障碍。我们的长期目标是通过调节遗传毒性NF-kappab信号通路来提高无线电/化学疗法的疗效并降低癌细胞的耐药性。我们以前的研究建立了一种保守的核对胞质信号传导途径，该途径策划了由广泛的遗传毒性治疗剂引起的NF-kappab激活。我们发现麋鹿（一种富含谷氨酸，亮氨酸，赖氨酸和丝氨酸的蛋白质）对于通过遗传毒性剂激活IKK复合物和NF-kappab是必不可少的。我们的初步研究表明，诸如泛素化和磷酸化之类的麋鹿的翻译后修饰协调了ATM依赖性IKK激活的过程，从而响应基因毒性治疗剂而导致NF-kappab激活。麋鹿的遗传消融显着增加了暴露于离子辐射的小鼠的死亡率。我们假设翻译后DNA损伤引起的麋鹿在遗传毒性NF-kappab信号通路中起着关键作用，并且调节遗传毒性NF-kappab激活可能会使肿瘤细胞对遗传毒性剂诱导的细胞死亡敏感。我们将以以下特定目的检验假设：目标1是表征麋鹿在遗传毒性NF-kappab信号通路中的泛素化。在AIM 2中，我们将描述ATM如何调节遗传毒性应激引起的麋鹿泛素化。我们将进一步确定麋鹿介导的DNA损伤反应的生物学功能及其对AIM3体内治疗性抗性的影响。该赠款提案中概述的拟议特定目的的完成将提高我们对控制麋鹿介导的遗传毒性NF-kappab信号及其在调节治疗抗性方面的功能的理解。此外，ATM的非神经功能的探索和ATM的潜在细胞质活性可能揭示了新型的研究范式，这可能会大大扩展我们在这些重要分子的生理和病理功能方面的知识。我们通过靶向特定的信号传导机制来设想对NF-kappab活性的选择性抑制，这将有效地减轻治疗性耐药性，同时保持癌症患者的免疫反应完整。