Regulation of NF-kappaB by Small Ubiquitin-Like Modifiers

描述（由申请人提供）：NF-？B/Rel家族转录因子参与关键的细胞过程，包括免疫、炎症和细胞生存反应。因此，NF-？B参与免疫相关疾病，如自身免疫，以及多种类型的人类恶性肿瘤。了解NF-？B调节不仅将扩大我们对基本细胞信号传导过程的认识，而且还将为预防和/或治疗这些人类疾病提供潜在的途径。在过去的二十年里，大量的文献描述了泛素在调节NF-？B的功能，我们对NF-？B信号通过另一种翻译后修饰剂SUMO（小泛素样修饰剂）传递。该项目的长期目标是大大扩展我们对NF-？B和SUMO在特定生理病理过程中的调控。我们最近发现了NEMO (NF-?) summoylation的一个新的信号作用。B本质调制器)在NF-？B信号。我们的初步数据表明，在SUMO和NF-?之间存在着重要的、新的串扰机制。B通路。因此，在本提案中，我们将检验相扑和NF-？B信号系统在调节某些生理和病理过程中起关键作用。这项研究有望大大扩展我们对SUMO和NF-？B通路及其在特定生理和病理过程中的作用。这项研究还将产生新的试剂和工具，使其他研究人员能够研究SUMO和NF-？相似和不同实验模型中的B信号系统。最后，它还可以确定针对人类疾病（如自身免疫和特定类型的恶性肿瘤）的药物开发的合理靶点。

DESCRIPTION (provided by applicant): The NF-?B/Rel family of transcription factors contributes to critical cellular processes, including immune, inflammatory and cell survival responses. As such, NF-?B is implicated in immunity-related diseases, such as autoimmunity, as well as multiple types of human malignancies. Understanding mechanisms of NF-?B regulation will not only expand our knowledge of basic cell signaling processes but also provide potential avenues to prevent and/or treat these human disorders. While a large body of literature over the last two decades describes the critical roles of ubiquitin in regulating NF-?B functions, very little is known about regulation of NF-?B signaling by SUMO (small ubiquitin-like modifier), another posttranslational modifier. The long-term goal of this project is to greatly expand our understanding of the mechanisms of NF-?B and SUMO regulation in specific physiological and pathological processes. We have recently uncovered a novel signaling role for SUMOylation of NEMO (NF-?B essential modulator) in NF-?B signaling. Our preliminary data indicate that there exist significant, novel crosstalk mechanisms between the SUMO and NF-?B pathways. Thus, in this proposal, we will test the hypothesis that crosstalk between SUMO and NF-?B signaling systems plays critical roles in regulating certain physiological and pathological processes. This research is expected to considerably expand our knowledge of the molecular links between SUMO and NF-?B pathways and their roles in specific physiological and pathological processes. This research will also generate novel reagents and tools to allow other researchers to investigate SUMO and NF-?B signaling systems in similar and different experimental models. Finally, it may also identify rational targets for drug development against human disorders, such as autoimmunity and specific types of malignancies. PUBLIC HEALTH RELEVANCE: The regulation of cancer cell death is a complex process involving many different molecular pathways. This research seeks to understand the relationships between protein modification by SUMO (Small Ubiquitin-like Modifier) and NF-?B signaling, one of the major cell death-regulatory pathways. This study will significantly expand our understanding of the regulatory mechanisms for normal and cancer cell death signaling, and may also provide rationale targets for the development of new anticancer drugs.