Regulation of NF-kappaB by Small Ubiquitin-Like Modifiers

小泛素样修饰剂对 NF-kappaB 的调节

基本信息

批准号：
8098970
负责人：
SHIGEKI MIYAMOTO
金额：
$ 28.67万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8098970
关键词：
Antineoplastic Agents Autoimmunity B Cell Proliferation B-Lymphocytes Breast Cancer Cell Cell Death Cell Death Signaling Process Cell Proliferation Cell Signaling Process Cell Survival Cell physiology Complex Data Defect Development Disease Experimental Models Family Germ-Line Mutation Goals Human Immune Immunity Inflammatory Knowledge Link Literature Malignant Neoplasms Malignant neoplasm of prostate Molecular Mus NF-kappa B Normal Cell Pathologic Processes Pathway interactions Peptide Hydrolases Physiological Processes Play Post-Translational Protein Processing Process Reagent Regulation Regulatory Pathway Research Research Personnel Role Signal Pathway Signal Transduction Signaling Protein Site Stress System Testing Ubiquitin cancer cell drug development malignant breast neoplasm mutant novel overexpression prevent public health relevance response tool transcription factor tumor

项目摘要

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.

描述（由申请人提供）：转录因子的NF-？b/rel家族有助于关键的细胞过程，包括免疫，炎症和细胞存活反应。因此，NF-？B与免疫相关疾病（例如自身免疫性以及多种类型的人类恶性肿瘤）有关。了解NF- b调节的机制不仅会扩大我们对基本细胞信号过程的了解，而且还提供了预防和/或治疗这些人类疾病的潜在途径。尽管在过去的二十年中，大量文献描述了泛素在调节Nf- b函数中的关键作用，但对于Sumo（小型泛素样修饰符）的NF-？b信号传导的调节，另一个是转移后的修饰仪，对NF-？B信号的调节知之甚少。该项目的长期目标是极大地扩展我们对特定生理和病理过程中NF-？B和SUMO调节机制的理解。最近，我们发现了NF-信号传导中Nemo（NF-？B ESSECTER调制器）的Sumoylation（NF-？B ESSECTER调制器）的新型信号传导作用。我们的初步数据表明，相扑和NF- b途径之间存在重要的新型串扰机制。因此，在此提案中，我们将检验以下假设：Sumo和NF-？B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。预计这项研究将大大扩展我们对Sumo和NF-途径之间的分子联系及其在特定生理和病理过程中的作用的知识。这项研究还将生成新颖的试剂和工具，以允许其他研究人员在类似和不同的实验模型中研究SUMO和NF-？B信号系统。最后，它还可以确定针对人类疾病的药物开发的合理目标，例如自身免疫性和特定类型的恶性肿瘤。公共卫生相关性：癌细胞死亡的调节是一个复杂的过程，涉及许多不同的分子途径。这项研究试图了解相扑（小泛素样修饰符）和NF- b信号传导的蛋白质修饰之间的关系，这是主要的细胞死亡调节途径之一。这项研究将大大扩展我们对正常和癌细胞死亡信号的调节机制的理解，还可能为开发新抗癌药物提供基本原理。