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

描述（由申请人提供）：COP9信号体（CSN）复合物是一种进化上保守的蛋白质复合物，存在于所有真核生物中，并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的关键细胞功能产生巨大影响，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。最近发现CSN复合体参与了NF-？B被细胞信号激活。但充分了解信号诱导的NF-中CSN复合物的功能和调控？缺乏B激活途径。NF - ?B蛋白是诱导转录因子，是许多生理和病理生理过程的重要调节因子。NF-?的异常调节B和控制其活性的信号通路（如TNFa通路）参与了癌症的发生和发展，以及对化疗和放疗的耐药性。因此,NF - ?B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关键重要性，我们假设对NF-？B通路不仅将提供对其功能和调控的新见解，而且还将为未来开发针对NF-？B系统通过CSN复合体。为了验证这一点，我们提出实现以下具体目标：1)定义人类CSN复合物与NF-？TNFa信号触发B活化。2)表征CSN5磷酸化和CSN5- ikk复合物对TNFa信号的动态相互作用。提出的工作代表了信号通路背景下CSN复合体的第一个详细的蛋白质组学分析。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。

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.