Gene-specific responses to NF-kB through lysine and arginine methylation of p65

通过 p65 的赖氨酸和精氨酸甲基化对 NF-kB 进行基因特异性反应

• 批准号: 10393362
• 负责人: Tao Lu
• 金额: $ 1.16万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10393362
• 关键词: Affect; Arginine; Binding; Biological; Cardiovascular Diseases; Cells; DNA; DNA Sequence; Development; Diabetes Mellitus; Disease; Ensure; Enzymes; Event; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Goals; Histones; Immune response; Inflammation; Lead; Link; Lung diseases; Lysine; Malignant Neoplasms; Methylation; Molecular; NF-kappa B; Nuclear; Pathologic; Pathology; Pharmaceutical Preparations; Regulation; Stress; Structure; Testing; Therapeutic Intervention; chronic inflammatory disease; innovation; insight; novel; novel therapeutics; p65; physical property; promoter; recruit; response; transcription factor

Project Abstract: Activation of the multi-functional transcription factor nuclear factor κB (NF-κB), a central coordinator of immune responses, is tightly regulated in order to achieve its normal transient activation in response to stress. In many pathologies, NF-κB is activated abnormally, contributing to the development of a variety of disorders, including lung disease, chronic inflammatory diseases, cardiovascular disease, diabetes, and cancer. Thus, drugs that block NF-κB activation could be effective in treating these diseases. Understanding the molecular mechanism of NF-κB activation is the first step toward our long-term goal of identifying novel therapeutics. This proposal focuses on methylation as a novel mechanism ensuring precise control of NF-κB activity at its target genes. Recently, we discovered that lysine residues 218/221 (K218/221) and arginine residue 30 (R30) of the p65 subunit of NF-κB are methylated by histone-modifying enzymes. Our central hypothesis is that p65 R30 and K218/221 methylation differentially regulates NF-κB-dependent gene expression by affecting promoter binding, recruitment of transcriptional modifiers, and the physical properties of the NF-κB:DNA interaction. To test this central hypothesis, we will pursue two specific aims: Aim 1: Dissect the distinct impacts of p65 R30 and K218/221 methylation on the critical molecular events that lead to differential gene regulation. Aim 2: Determine the structural consequences of p65 R30 methylation, and discover the mechanisms of NF-κB-DNA sequence specific effects on target gene promoters. Significance: The important findings from this study will identify the molecular mechanisms underlying p65 methylation-dependent gene-specific regulation, thus revealing how the extreme plasticity of biological responses is regulated by NF-κB, and offering deep insights into the development of NF-κB-associated diseases as well as innovative strategies for their therapeutic intervention.

项目摘要： 多功能转录因子核因子κB（NF-κB）的激活，是免疫调节的中心协调者， 反应，是严格调节，以实现其正常的瞬态激活响应压力。在许多 在病理学中，NF-κB被异常激活，导致多种疾病的发展，包括 肺病、慢性炎症性疾病、心血管疾病、糖尿病和癌症。因此， 阻断NF-κB活化可能是治疗这些疾病的有效方法。了解的分子机制 NF-κB的激活是我们实现长期目标的第一步，即确定新的治疗方法。这项建议 关注甲基化作为一种新的机制，确保精确控制NF-κB在其靶基因的活性。 最近，我们发现p65的赖氨酸残基218/221（K218/221）和精氨酸残基30（R30） NF-κB亚基被组蛋白修饰酶甲基化。我们的中心假设是p65 R30和 K218/221甲基化通过影响启动子结合差异调节NF-κ B依赖性基因表达， 转录调节因子的募集以及NF-κB：DNA相互作用的物理性质。为了验证这一 中心假设，我们将追求两个具体的目标：目标1：剖析p65 R30的不同影响， K218/221甲基化对导致差异基因调控的关键分子事件的影响。目标2：确定 p65 R30甲基化的结构后果，并发现NF-κB-DNA序列的机制 对靶基因启动子的特异性作用。意义：这项研究的重要发现将确定 p65甲基化依赖的基因特异性调控的分子机制，从而揭示了 NF-κB调控着生物反应的高度可塑性，这为深入了解NF-κB的发展提供了新的视角。 NF-κ B相关疾病及其治疗干预的创新策略。

项目成果

The Pivotal Player: Components of NF-κB Pathway as Promising Biomarkers in Colorectal Cancer.

• DOI: 10.3390/ijms22147429
• 发表时间: 2021-07-11
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Martin M;Sun M;Motolani A;Lu T
• 通讯作者: Lu T

The Pivotal Role of NF-kB in the Pathogenesis and Therapeutics of Alzheimer's Disease.

NF-kB 在阿尔茨海默病的发病机制和治疗中的关键作用。

• DOI: 10.3390/ijms23168972
• 发表时间: 2022-08-11
• 期刊: International journal of molecular sciences
• 影响因子: 5.6

Phosphorylation of the Regulators, a Complex Facet of NF-κB Signaling in Cancer.

• DOI: 10.3390/biom11010015
• 发表时间: 2020-12-26
• 期刊: Biomolecules
• 影响因子: 5.5
• 作者: Motolani A;Martin M;Sun M;Lu T
• 通讯作者: Lu T

Using VBIM Technique to Discover ARMC4/ODAD2 as a Novel Negative Regulator of NF-κB and a New Tumor Suppressor in Colorectal Cancer.

• DOI: 10.3390/ijms23052732
• 发表时间: 2022-03-01
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Martin M;Mundade R;Hartley AV;Jiang G;Jin J;Sun S;Safa A;Sandusky G;Liu Y;Lu T
• 通讯作者: Lu T

Genetic Alterations of NF-κB and Its Regulators: A Rich Platform to Advance Colorectal Cancer Diagnosis and Treatment.

• DOI: 10.3390/ijms25010154
• 发表时间: 2023-12-21
• 期刊: International journal of molecular sciences
• 影响因子: 5.6