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

基本信息

批准号：
8303937
负责人：
Lan Huang
金额：
$ 20.02万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8303937
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

项目摘要

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. PUBLIC HEALTH RELEVANCE: Project Narrative Disregulation of the NF-?B pathway can lead to many human diseases including cancer. The CSN complex is a multi-subunit complex that is involved in regulating turmorigenesis and is associated with NF-?B activation. Detailed characterization of the CSN complex in the NF-?B pathway will allow the identification of potential molecular targets for improved cancer therapeutics.

描述（由申请人提供）：COP9信号体（CSN）复合物是存在于所有真核生物中的进化保守的蛋白质复合物，并且参与控制多种细胞和发育过程。 CSN 复合体的失调会对肿瘤发展至关重要的细胞功能产生巨大影响，包括 DNA 保真度的维持、细胞周期控制、DNA 修复、血管生成和微环境稳态。最近发现 CSN 复合物参与细胞外信号传导激活的 NF-κB 的调节。但对 CSN 复合物在信号诱导的 NF-κB 激活途径中的功能和调节尚缺乏充分的了解。 NF-κB 蛋白是诱导型转录因子，是许多生理和病理生理过程的关键调节因子。 NF-κB 和控制其活性的信号通路（例如 TNFa 通路）的异常调节与癌症的发生和进展以及对化疗和放疗的抵抗有关。因此，NF-κB和参与调节其活性的成分已成为药物发现的焦点。鉴于其在癌症发展中的至关重要性，我们假设对 NF-κB 通路中 CSN 复合物的详细分析不仅将为其总体功能和调节提供新的见解，而且还将为临床有用的药物的未来开发带来新的方向。通过 CSN 复合物靶向 NF-κB 系统的癌症治疗抑制剂。为了测试这一点，我们建议实现以下具体目标：1）定义与 TNFa 信号传导触发的 NF-κB 激活相关的人类 CSN 复合体的蛋白质相互作用动力学。 2) 表征 CSN5 磷酸化和 CSN5-IKK 复合物对 TNFa 信号传导的动态相互作用。这项工作代表了在信号通路背景下对 CSN 复合物的首次详细蛋白质组学分析。这项工作中开发的方法将适用于响应细胞外信号传导的其他蛋白质复合物的研究。公共健康相关性：项目叙述 NF-κB 通路的失调可导致包括癌症在内的许多人类疾病。 CSN 复合体是一种多亚基复合体，参与调节肿瘤发生并与 NF-κB 激活相关。 NF-κB 通路中 CSN 复合物的详细表征将有助于识别改进癌症治疗的潜在分子靶点。