Gene Specific Regulation of NFkB by Nuclear IkBa in Inflammation and Cancer

炎症和癌症中核 IkBa 对 NFkB 的基因特异性调控

基本信息

批准号：
7778063
负责人：
Ivana Vancurova
金额：
$ 24.53万
依托单位：
ST. JOHN'S UNIVERSITY
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：
2010-03-01 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7778063
关键词：
Anti-Inflammatory Agents Anti-inflammatory Apoptosis Apoptotic Binding Biomedical Research Bortezomib Cell physiology Cells DNA Binding Data Development Disease Drug Delivery Systems Environment Event Figs - dietary Gene Expression Genes Genetic Transcription Goals Human IL8 gene In Vitro Inflammation Inflammatory Interleukin-12 Interleukin-6 Lead Learning Leukocytes Malignant Neoplasms Measures Modeling Molecular Nuclear Nuclear Translocation Phosphorylation Post-Translational Protein Processing Proteasome Inhibition Proteins Regulation Research Specificity Students T-Cell Leukemia TNF gene Testing Universities Work base cancer cell cancer therapy chromatin immunoprecipitation cytokine dimer human disease in vivo inhibitor/antagonist leptomycin B leukemia macrophage multicatalytic endopeptidase complex novel p65 promoter protein B public health relevance research study therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Our long-term goal is to understand the mechanisms regulating transcription of NF?B-dependent anti-apoptotic and pro-inflammatory genes. Since NF?B activity and expression of NF?B-regulated pro-inflammatory and anti-apoptotic genes are increased in many inflammatory diseases, as well as in many types of human cancer and leukemia, inhibition of NF?B-dependent transcription thus represents an important therapeutic target. However, one of the main concerns regarding the NF?B inhibitors is their specificity, since many steps leading to NF?B activation are important for other cellular functions as well. Our previous studies have shown that an induction of nuclear translocation and accumulation of the NF?B inhibitor, I?B?, inhibits the in vitro NF?B DNA binding activity and induces apoptosis in human leukocytes and cancer cells. Importantly, our recent data indicate that the in vivo inhibition of NF?B-dependent transcription by nuclear I?B? is gene specific: while the transcription of pro-inflammatory cytokines TNF?, IL-12 and IL-6 in human leukocytes is inhibited by nuclear I?B?, transcription of IL-8 is not. However, at present, the mechanisms that regulate the in vivo nuclear interaction of I?B? with NF?B proteins and NF?B- dependent promoters are unknown. The central hypothesis of this proposal is that the regulation of NF?B-dependent transcription of pro-inflammatory and anti-apoptotic genes by nuclear I?B? is gene specific, and could thus provide a basis for novel anti-inflammatory and anti-cancer therapies aimed at the specific inhibition of NF?B activity by nuclear I?B?. The specific aims focus on analyzing the mechanisms that regulate the in vivo binding of I?B? to NF?B dimers and NF?B promoters, thus regulating NF?B-dependent transcription. In Aim 1, we will measure by chromatin immunoprecipitation the recruitment of NF?B and I?B? proteins to NF?B-regulated promoters of pro-inflammatory and anti-apoptotic genes in human U937 macrophages and leukemia Hut-78 cells. We will determine whether the ability of nuclear I?B? to inhibit NF?B-dependent transcription depends on the subunit composition of NF?B dimers. In Aim 2, we will identify the mechanisms that regulate the nuclear I?B?-NF?B interaction in U937 macrophages and Hut-78 leukemia cells, and we will test the hypothesis that the responsible mechanisms involve post-translational modification(s) of p65 NF?B, and/or gene specific recruitment of the proteasome. Identification of the mechanisms that regulate the gene specific transcription of NF?B-dependent genes by nuclear I?B? might provide a new strategy that would use the nuclear I?B? as a specific regulator of NF?B-dependent transcription. This approach could be applicable in both anti-inflammatory and anti-cancer therapies. In addition, this project will enhance the research environment at St. John's University by providing undergraduate students with numerous opportunities to learn the fundamentals of biomedical research. PUBLIC HEALTH RELEVANCE: This proposal focuses on the mechanisms that regulate ability of the nuclear inhibitory protein I?B? to associate with NF?B-regulated promoters and inhibit transcription of NF?B-dependent inflammatory and pro-survival genes. Since NF?B activity is increased in many human diseases including inflammatory disorders, cancer, and leukemia, identification of the mechanisms by which the nuclear I?B? inhibits NF?B-dependent transcription will lead to the development of more specific anti-inflammatory and anti-cancer therapies.

描述（由申请人提供）：我们的长期目标是了解调节 NFκB 依赖性抗凋亡和促炎症基因转录的机制。由于 NFκB 活性以及 NFκB 调节的促炎和抗凋亡基因的表达在许多炎症性疾病以及许多类型的人类癌症和白血病中增加，因此抑制 NFκB 依赖性转录代表一个重要的治疗靶点。然而，关于 NFκB 抑制剂的主要问题之一是它们的特异性，因为导致 NFκB 激活的许多步骤对于其他细胞功能也很重要。我们之前的研究表明，诱导核易位和NFκB抑制剂IκB的积累，可抑制体外NFκB DNA结合活性并诱导人类白细胞和癌细胞凋亡。重要的是，我们最近的数据表明核 I?B 对 NF?B 依赖性转录的体内抑制？具有基因特异性：虽然人类白细胞中促炎细胞因子 TNF?、IL-12 和 IL-6 的转录受到核 I?B? 的抑制，但 IL-8 的转录则不然。然而，目前调节I?B体内核相互作用的机制尚不清楚。与 NF?B 蛋白和 NF?B 依赖性启动子的关系尚不清楚。该提议的中心假设是核 I?B 调节促炎和抗凋亡基因的 NF?B 依赖性转录？是基因特异性的，因此可以为旨在通过核 IκB 特异性抑制 NFκB 活性的新型抗炎和抗癌疗法提供基础。具体目标是分析调节 I?B? 体内结合的机制。 NF?B 二聚体和 NF?B 启动子，从而调节 NF?B 依赖性转录。在目标 1 中，我们将通过染色质免疫沉淀测量 NF?B 和 I?B？人类 U937 巨噬细胞和白血病 Hut-78 细胞中促炎和抗凋亡基因的 NFκB 调节启动子的蛋白质。我们将确定核I?B是否有能力？抑制 NF?B 依赖性转录取决于 NF?B 二聚体的亚基组成。在目标 2 中，我们将确定 U937 巨噬细胞和 Hut-78 白血病细胞中调节核 I?B?-NF?B 相互作用的机制，并且我们将检验相关机制涉及翻译后修饰的假设p65 NFκB 的作用，和/或蛋白酶体的基因特异性募集。通过核 I?B? 鉴定调节 NF?B 依赖基因的基因特异性转录的机制可能会提供一种使用核 I?B 的新策略？作为 NF?B 依赖性转录的特异性调节因子。这种方法可适用于抗炎和抗癌治疗。此外，该项目将为本科生提供大量学习生物医学研究基础知识的机会，从而改善圣约翰大学的研究环境。公共健康相关性：该提案重点关注调节核抑制蛋白 I?B? 能力的机制。与 NF?B 调节的启动子结合并抑制 NF?B 依赖性炎症和促生存基因的转录。由于 NFκB 活性在许多人类疾病中增加，包括炎症性疾病、癌症和白血病，因此需要确定核 IκB 激活的机制。抑制 NF?B 依赖性转录将导致更特异的抗炎和抗癌疗法的开发。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Bortezomib inhibits expression of TGF-β1, IL-10, and CXCR4, resulting in decreased survival and migration of cutaneous T cell lymphoma cells.

DOI：
10.4049/jimmunol.1402610
发表时间：
2015-03-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Chang TP;Poltoratsky V;Vancurova I
通讯作者：
Vancurova I

Bcl3 regulates pro-survival and pro-inflammatory gene expression in cutaneous T-cell lymphoma.

DOI：
10.1016/j.bbamcr.2014.07.012
发表时间：
2014-11
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
影响因子：
5.1
作者：
Chang, Tzu-Pei;Vancurova, Ivana
通讯作者：
Vancurova, Ivana

Proteasome inhibition by bortezomib increases IL-8 expression in androgen-independent prostate cancer cells: the role of IKKα.

DOI：
10.4049/jimmunol.1300895
发表时间：
2013-09-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Manna S;Singha B;Phyo SA;Gatla HR;Chang TP;Sanacora S;Ramaswami S;Vancurova I
通讯作者：
Vancurova I

Anti-inflammatory actions of endogenous and exogenous interleukin-10 versus glucocorticoids on macrophage functions of the newly born.