Novel roles of IKK complex to program gene expression

IKK 复合物在基因表达编程中的新作用

• 批准号: 6682474
• 负责人: KENNETH B MARCU
• 金额: $ 31.27万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6682474
• 关键词: DNA binding protein; I kappa B beta; biological signal transduction; cell cycle; cell growth regulation; chromosomes; cytokine; gene expression; gene induction /repression; laboratory mouse; microarray technology; mutant; nuclear factor kappa beta; polymerase chain reaction; protein structure function; stress; transcription factor

The NF-KappaB inducing IKK signalsome complex is the final receiver and integrator of a host of extracellular stress-like and inflammatory response stimuli. The IKK complex consists of two serinelthreonine kinases (IKKalpha and IKKbeta) and a con-catalytic regulatory/docking protein (NEMO/IKKy). IKK(3 and NEMO/IKKgamma are essential for inducing NF-KB nuclear translocation and DNA binding activity in response to mediators of inflammatory responses like TNFalpha and IL-1, while IKKalpha is largely believed to be dispensible for activating NF-KappaB by these stimuli. Surprisingly, we have recently found that IKKalpha is essential for inducing the transcriptional competence of nuclear NF-KappaB subunits in response to inflammatory cytokines, implying that it plays a critical role in activating NF-KB independent of its DNA binding activity. Consequently, one aim of this proposal will be to elaborate the molecular requirements and mechanisms of action of IKKalpha as a co-global mediator (along with IKKbeta and NEMO/IKKgamma) of stress-like responses culminating in NF-kappaB activation. We have also discovered that the IKK signalsome simultaneously co-ordinates the global induction and repression of cellular gene expression. In a second aim we will elaborate the mechanisms of action of the IKK signalsome as a mediator of NF-KappaB dependent gene repression. We have hypothesized that IKK mediated NF-KappaB activation operates like a co-ordinately controlled on/off switch that alters physiological responses in vivo. Interestingly a subset of the genes, which are repressed in response to extracellular stimulus dependent and IKK mediated NF-KB activation, are also induced targets of the E2F-I. E2F-1 is capable of inducing cell cycle arrest, apoptosis and cell cycle progression depending on its degree of activation and the physiological state of the cell. Experimental conditions in primary and established cells will be established, which lead to interference between NF-KB and E2F on specific genomic targets. The physiological effects of IKK/NF-KappaB mediated repression of cell cycle regulated, E2F target genes will also be evaluated.

NF-κ B诱导IKK信号体复合物是细胞外应激样和炎症反应刺激的最终受体和整合剂。IKK复合物由两种丝氨酸/苏氨酸激酶（IKK α和IKK β）和共催化调节/对接蛋白（NEMO/IKKy）组成。IKK β和NEMO/IKK γ是诱导NF-κ B核转位和DNA结合活性所必需的，以响应炎症反应的介质如TNF α和IL-1，而IKK α在很大程度上被认为是通过这些刺激激活NF-κ B所必需的。令人惊讶的是，我们最近发现IKK α对于诱导 这表明核NF-κ B亚基在响应炎性细胞因子中的转录能力，这意味着它在激活NF-κ B中起关键作用，而不依赖于其DNA结合活性。因此，本建议的一个目的是阐述IKK α作为共同的全球调解人（沿着IKK β和NEMO/IKK γ）的应激样反应，最终在NF-κ B激活的分子要求和机制。 我们还发现IKK信号体同时协调细胞基因表达的整体诱导和抑制。在第二个目标中，我们将阐述IKK信号体作为NF-κ B依赖性基因抑制的介体的作用机制。我们假设IKK介导的NF-κ B激活作用类似于一个协调控制的开/关开关，改变体内的生理反应。有趣的是，响应于细胞外刺激依赖性和IKK介导的NF-κ B活化而被抑制的基因的子集也是E2 F-I的诱导靶标。E2 F-1能够诱导细胞周期停滞、凋亡和细胞周期进展，这取决于其表达的程度。 激活和细胞的生理状态。将建立原代细胞和已建立细胞中的实验条件，其导致NF-κ B和E2 F之间对特定基因组靶标的干扰。还将评价IKK/NF-KappaB介导的细胞周期调节的E2 F靶基因阻遏的生理作用。