REGULATION OF NF-KAPPA B

生物体的生长、分化和发育受到空间和空间的严格控制 转录因子的时间调节。核因子-KB蛋白是一个转录因子大家族， 控制与免疫反应、癌症、病毒感染、 细胞程序性死亡、发育线索等。与大多数转录因子不同，核因子-KB蛋白是 与抑制蛋白(1Kbs)结合在细胞质中。响应于外部信号， 1KB蛋白被蛋白酶体磷酸化、泛素化和降解，从而允许释放 核因子-KB蛋白到细胞核，在那里它们可以结合到同源DNA结合部位并激活转录 特定的基因。核因子-KB蛋白对外界刺激的反应中的开创性事件是 1kb蛋白的降解。在这项提案中，我们计划研究一个大型 细胞质复合体，称为IKK，接收信号并调节1KB的降解 蛋白。我们计划了解IKK中存在的两个激酶IKK1和IKK2的分子功能 复杂的是因为它们在唯一的残基上磷酸化iKBcc以触发其降解过程。我们有 产生的小鼠中，这两种激酶要么单独删除，要么同时删除。这个 这些激酶对小鼠发育的显著但相当不同的影响使我们不禁要问，这些激酶 在生长和发育中扮演着截然不同的角色。我们计划研究它的性质和机制。 双“基因敲除”小鼠的脑畸形(IKK1和IKK2都被移除)。我们还将研究什么 在不同的组织中，这些激酶中的每一个都有特定的信号通路做出反应。利用新型DNA微阵列 技术(可以同时分析数千个基因)我们将识别由核因子诱导的新基因- KB蛋白与细胞生长和程序性细胞死亡(细胞凋亡)。我们还计划确定两人是否 除了诱导1kb蛋白的磷酸化外，还参与了其他功能。最后，我们还 建议构建含有突变型IKKS或1KB蛋白的病毒载体，并研究其对 实验性模型系统，如哮喘、类风湿性关节炎、癌症模型(辐射损伤、化疗毒性 代理商)和开发。我们相信，这里提出的实验将使我们能够破译 核因子-KB蛋白调控的分子机制。对这一重要信号的详细了解 路径将使我们能够开发治疗从炎症到癌症的各种疾病的策略。

Growth, differentiation, and development of an organism is tightly controlled by the spatial and temporal regulation of transcription factors. NF-KB proteins are a large family of transcription factors which control the expression of a vast array of genes involved in immune response, cancer, viral infections, programmed cell death, developmental clues, etc. Unlike most transcription factors, NF-KB proteins are sequestered in the cytoplasm in association with inhibitory proteins (1KBs). In response to an external signal, the 1KBproteins are phosphorylated, ubiquitinated, and degraded by proteosomes to allow the release of the NF-KB protein to the nucleus where they can bind to the cognate DNA binding sites and activatetranscription of specific genes. The seminal event in the activation of NF-KB proteins in response to exogenous stimulus is the degradation of 1KB proteins. In this proposal we are planning to study the components of a large cytoplasmic complex, referred to as IKK, which receives the signal and modulates the degradation of1KB protein. We plan to understand the molecular function of the two kinases, IKK1 and IKK2 present in the IKK complex because they phosphorylate iKBcc at unique residues to trigger its degradation process. We have generated mice where the two kinases have been genetically deleted either singly or both of them. The remarkable but quite distinct influences of these kinases on mice development lead us to ask if these kinases have distinctly different roles in growth and development. We plan to study the nature and mechanism of brain malformation in double "knockout" mice (both IKK1 and IKK2 are removed). We will also study what specific signal pathways each of these kinases respond to in different tissues. By using novel DNA microarray technology (thousands of genes can be analyzed simultaneously) we will identify novel genes induced by NF- KB proteins in cell growth and programmed cell death (apoptosis). We also plan to determine if the two kinases are involved in functions other than induced phosphorylation of 1KB proteins. Finally, we also propose to generate viral vectors containing mutant forms of IKKs or 1KBproteins and study their effect on experimental model systems like asthma, rheumatoid arthritis, cancer models (radiation damage, chemotoxic agents), and development. We believe that the experiments proposed here will allow us to decipher the molecular mechanism of regulation of NF-KB proteins. The detailed knowledge of this important signal pathway will allow us to develop strategies for curing diseases ranging from inflammation to cancer.