Regulation of NF-kappaB by Small Ubiquitin-Like Modifiers

小泛素样修饰剂对 NF-kappaB 的调节

• 批准号: 8505491
• 负责人: SHIGEKI MIYAMOTO
• 金额: $ 27.66万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 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/8505491
• 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

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）：NF-？转录因子的B/Rel家族有助于关键的细胞过程，包括免疫、炎症和细胞存活应答。因此，NF-？B涉及免疫相关疾病，如自身免疫，以及多种类型的人类恶性肿瘤。了解NF-？B调节不仅将扩展我们对基本细胞信号传导过程的知识，而且还提供预防和/或治疗这些人类疾病的潜在途径。虽然在过去的二十年里，大量的文献描述了泛素在调节NF-κ B中的关键作用？B的功能，很少有人知道调节NF-？B信号通过SUMO（小泛素样修饰物），另一种翻译后修饰物。这个项目的长期目标是大大扩展我们对NF-？B和SUMO在特定生理和病理过程中的调节作用。我们最近发现了NEMO（NF-？B必需调节剂）在NF-？B信令。我们的初步数据表明，存在显着的，新的串扰机制之间的相扑和NF-？B途径。因此，在这项建议中，我们将测试的假设，相扑和NF-？B信号系统在调节某些生理和病理过程中起着关键作用。这项研究预计将大大扩大我们的知识之间的分子联系相扑和NF-？B途径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，让其他研究人员调查相扑和NF-？B信号系统在相似和不同的实验模型。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）的药物开发的合理目标。 公共卫生相关性：调节癌细胞死亡是一个复杂的过程，涉及许多不同的分子途径。本研究旨在了解蛋白质修饰SUMO（小泛素样修饰剂）和NF-？B信号传导是细胞死亡的主要调控途径之一。这项研究将大大扩展我们对正常细胞和癌细胞死亡信号转导的调控机制的理解，也可能为开发新的抗癌药物提供合理的靶点。

项目成果

Chromatin-bound IκBα regulates a subset of polycomb target genes in differentiation and cancer.

• DOI: 10.1016/j.ccr.2013.06.003
• 发表时间: 2013-08-12
• 期刊: Cancer cell
• 影响因子: 50.3
• 作者: Mulero MC;Ferres-Marco D;Islam A;Margalef P;Pecoraro M;Toll A;Drechsel N;Charneco C;Davis S;Bellora N;Gallardo F;López-Arribillaga E;Asensio-Juan E;Rodilla V;González J;Iglesias M;Shih V;Mar Albà M;Di Croce L;Hoffmann A;Miyamoto S;Villà-Freixa J;López-Bigas N;Keyes WM;Domínguez M;Bigas A;Espinosa L
• 通讯作者: Espinosa L