Functional studies on the kB-Ras proteins

κB-Ras1和2是两个进化保守的ras样蛋白。它们在某些氨基酸上与经典Ras蛋白不同，否则只在Ras的致癌形式中发现，并且没有典型的法尼基化位点。这表明它们的功能可能与传统的Ras GTPases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的激活。NF-κB活性主要受抑制蛋白i -κB α和i -κB β调控。κB-Ras蛋白特异性地与i - κ b β相互作用，并干扰其刺激诱导的降解。因此，κB-Ras蛋白可能解释了所观察到的i -κB β的延迟和不完全降解，这是持续NF-κB活性所必需的。在这里，我建议表征κB-Ras缺陷小鼠，以建立对体内κB-Ras蛋白整体生物学作用的理解。我的研究旨在阐明NF-κB信号传导中κB-Ras功能的分子机制，以及这些蛋白在NF-κB依赖性过程（如免疫反应或造血恶性肿瘤的发展）中由此产生的生理作用。

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.