Functional studies on the kB-Ras proteins

κB-RAS 1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的RAS蛋白不同，否则只在RAS的致癌形式中发现，并且缺乏典型的法尼化位点。这表明它们的功能可能与经典的RAS GTP酶截然不同。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的活性主要受抑制蛋白IκBα和IκBβ调节。κB-RAS蛋白与IκBβ特异地相互作用，干扰刺激诱导的降解。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，这是持续的NF-κB活性所必需的。在这里，我建议对κB-RAS缺陷小鼠进行表征，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κB-RAS在核因子-κB信号转导中的分子机制，以及这些蛋白在免疫反应或恶性血液病发生等依赖于核因子-κB的过程中的生理作用。

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.