Regulation of NF-kappaB by Small Ubiquitin-Like Modifiers

描述(由申请人提供)：核因子-？B/Rel转录因子家族参与关键的细胞过程，包括免疫、炎症和细胞生存反应。因此，核因子-β与免疫相关的疾病，如自身免疫，以及多种类型的人类恶性肿瘤有关。了解核因子？B的调控机制不仅将扩大我们对基本细胞信号传递过程的了解，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，大量文献描述了泛素在调节核因子-βB功能中的关键作用，但对另一种翻译后修饰因子SUMO(小泛素样修饰物)对核因子-βB信号的调控知之甚少。该项目的长期目标是极大地扩大我们对核因子-β和相扑在特定生理和病理过程中的调节机制的理解。我们最近发现了NEMO(核因子-？B必需调节剂)在核因子-？B信号中的一种新的信号作用。我们的初步数据表明，在相扑和核因子？B通路之间存在显著的、新颖的串扰机制。因此，在这项提议中，我们将检验相扑和核因子-β信号系统之间的串扰在调节某些生理和病理过程中起关键作用的假设。这项研究有望极大地扩展我们对相扑和核因子？B通路之间的分子联系以及它们在特定的生理和病理过程中的作用的认识。这项研究还将产生新的试剂和工具，使其他研究人员能够在类似和不同的实验模型中研究相扑和核因子？B信号系统。最后，它还可能确定针对人类疾病的药物开发的合理靶点，如自身免疫和特定类型的恶性肿瘤。 公共卫生相关性：癌细胞死亡的调控是一个复杂的过程，涉及许多不同的分子途径。这项研究试图了解SUMO(小泛素样修饰物)对蛋白质的修饰与主要的细胞死亡调节途径之一的核因子-β信号之间的关系。这项研究将极大地扩展我们对正常和癌细胞死亡信号调控机制的理解，也可能为开发新的抗癌药物提供理论靶点。

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.