Function and Regulation of the CSN in the NF-kB Activation Pathway

CSN 在 NF-kB 激活途径中的功能和调节

• 批准号: 8468669
• 负责人: Lan Huang
• 金额: $ 15.73万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8468669
• 关键词: Address; Adopted; Affinity; Biochemical; Biological; Biological Assay; Catalytic Domain; Cell Cycle Regulation; Cell Death; Cell Survival; Cell physiology; Cells; Complex; DNA Maintenance; DNA Repair; Development; Developmental Process; Eukaryota; Future; Genes; Homeostasis; Human; Immune response; Individual; Inflammation; Lead; Life; Link; Literature; Malignant Neoplasms; Mass Spectrum Analysis; Methodology; Methods; Molecular; Mutagenesis; Mutate; NF-kappa B; Oncogenic; Pathway Analysis; Pathway interactions; Phosphorylation; Physiological; Play; Process; Protein Dynamics; Protein p53; Proteins; Proteomics; Radiation therapy; Regulation; Reporting; Resistance; Role; Series; Signal Pathway; Signal Transduction; System; TNF gene; Testing; Therapeutic; Therapeutic Intervention; Work; angiogenesis; base; cancer therapy; cancer type; chemotherapy; crosslink; design; drug discovery; extracellular; improved; in vivo; inhibitor/antagonist; insight; novel; overexpression; protein B; protein complex; protein function; protein protein interaction; response; transcription factor; tumor

DESCRIPTION (provided by applicant): The COP9 signalosome (CSN) complex is an evolutionally conserved protein complex present in all eukaryotes and is involved in controlling diverse cellular and developmental processes. Disregulation of the CSN complex can have a dramatic effect on cellular functions critical to tumor development, including maintenance of DNA fidelity, cell cycle control, DNA repair, angiogenesis, and micro-environmental homeostasis. The CSN complex has recently been found to be involved in the regulation of NF-?B activated by excellular signaling. But a full understanding of the function and regulation of the CSN complex in signal-induced NF-?B activation pathways is lacking. NF-?B proteins are inducible transcription factors that are crucial regulators of many physiological and pathophysiological processes. Aberrant regulation of NF-?B and the signaling pathways (e.g. TNFa pathway) controlling its activity are involved in cancer development and progression, as well as resistance to chemotherapy and radiotherapy. Therefore, NF-?B and components involved in regulating its activity have become a focal point for drug discovery. Given its critica importance in cancer development, we hypothesize that detailed analysis of the CSN complex in the NF-?B pathway will not only provide new insights into its function and regulation in general, but also lead to new directions in future development of clinically useful inhibitors for cancer treatment targeting the NF-?B system through the CSN complex. To test this, we propose to achieve the following specific aims: 1) To define protein interaction dynamics of the human CSN complex associated with NF-?B activation triggered by TNFa signaling. 2) To characterize CSN5 phosphorylation and the dynamic interactions of the CSN5-IKK complex upon TNFa signaling. The proposed work represents the first detailed proteomic analysis of the CSN complex in the context of signaling pathways. The methodology developed in this work will be applicable for the study of other protein complexes in response to extracellular signaling.

描述（由申请人提供）：COP 9信号体（CSN）复合物是一种存在于所有真核生物中的进化上保守的蛋白质复合物，参与控制多种细胞和发育过程。CSN复合物的失调可以对肿瘤发展至关重要的细胞功能产生显著影响，包括维持DNA保真度、细胞周期控制、DNA修复、血管生成和微环境稳态。CSN复合物最近被发现参与NF-？B由细胞外信号激活。但对CSN复合物在信号诱导的NF-？缺乏B激活途径。NF-？B蛋白是诱导型转录因子，是许多生理和病理生理过程的重要调节因子。NF-？B和控制其活性的信号传导途径（例如TNF α途径）参与癌症的发生和进展，以及对化疗和放疗的抗性。因此，NF-？B和参与调节其活性的组分已成为药物发现的焦点。鉴于其critica的重要性，在癌症的发展，我们假设，详细分析的CSN复杂的NF-？B通路的研究不仅为了解其功能和调控机制提供了新的思路，而且为将来开发针对NF-？B系统通过CSN复合体。为了测试这一点，我们建议实现以下具体目标：1）定义与NF-？由TNF α信号传导触发的B激活。2)表征CSN 5磷酸化和CSN 5-IKK复合物在TNF α信号传导后的动态相互作用。拟议的工作代表了第一个详细的蛋白质组学分析的CSN复合物的背景下，信号通路。在这项工作中开发的方法将适用于其他蛋白质复合物响应细胞外信号的研究。