Functional studies on the kB-Ras proteins

kB-Ras 蛋白的功能研究

• 批准号: 89147004
• 负责人: Dr. Andrea Oeckinghaus
• 金额: --
• 依托单位: Department of Microbiology and Immunology
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2008
• 资助国家: 德国
• 起止时间: 2007-12-31 至 2010-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/89147004?language=en
• 关键词: Functional; studies; kB; Ras; proteins

κB-Ras1 and 2 are two evolutionary conserved Ras-like proteins. They differ from classical Ras proteins in certain amino acids, otherwise only found in the oncogenic forms of Ras, and in the absence of the typical farnesylation site. This suggests that they might function quite differently than classical Ras GTPases. Although little is known about the function of κB-Ras proteins, biochemical experiments have shown that they can interfere with activation of the transcription factor NF-κB. NF-κB activity is mainly regulated by the inhibitory proteins IκBα and IκBβ. κB-Ras proteins specifically interact with IκBβ and interfere with its stimulus-induced degradation. Thus, κB-Ras proteins might provide an explanation for the observed delayed and incomplete degradation of IκBβ, which is required for persistent NF-κB activity. Here I propose to characterize κB-Ras deficient mice to establish an understanding of the overall biological role of κB-Ras proteins in vivo. My studies aim to elucidate the molecular mechanisms of κB-Ras function in NF-κB signalling and the resulting physiological roles of these proteins in NF-κB dependent processes like the immune response or the development of hematopoetic malignancies.

κ B-Ras 1和2是两个进化上保守的Ras样蛋白。它们在某些氨基酸上不同于经典的Ras蛋白，否则仅在Ras的致癌形式中发现，并且不存在典型的法尼基化位点。这表明它们的功能可能与经典的Ras GTP酶完全不同。尽管对κB-Ras蛋白的功能知之甚少，但生化实验表明它们可以干扰转录因子NF-κB的活化。NF-κB活性主要受抑制蛋白IκBα和IκBβ的调节。κB-Ras蛋白特异性地与IκBβ相互作用并干扰其刺激诱导的降解。因此，κB-Ras蛋白可能为观察到的IκBβ延迟和不完全降解提供了解释，而IκBβ是持续NF-κB活性所必需的。在这里，我建议表征κB-Ras缺陷小鼠，以建立对κB-Ras蛋白在体内的整体生物学作用的理解。我的研究旨在阐明NF-κB信号转导中κB-Ras功能的分子机制，以及这些蛋白在NF-κB依赖性过程（如免疫反应或造血系统恶性肿瘤的发展）中的生理作用。