Regulation of NF-kapaB and IKK by proinflammatory stimuli

这是一个10岁的项目，其目标是了解继续申请 由IkB激酶（IKK）复合物控制的不同信号应答的调节和功能及其 三个亚基：IKKa、IKKb和IKKg。上一个项目期间取得了相当大的进展， 除了对IKK调节及其在NF-κ B活化中的作用的进一步理解，我们还阐明了IKK在NF-κ B活化中的作用。 两个IKK催化亚基（IKKa和IKKb）在先天免疫和炎症控制中的作用， 以及程序性细胞死亡、癌症、慢性炎性疾病和自身免疫。过程中 在这些研究中，我们取得了一些意想不到的、相当令人惊讶的发现，我们计划在更大的范围内继续研究。 在下一个项目期间详细。这些发现包括Hif 1a基因的鉴定，该基因编码 低氧调节HIF-1转录因子的HIF-1a亚基，作为IKKb和NF-κ B调节基因。 这些结果表明，除了其在抑制细胞凋亡和激活宿主防御中的关键作用外， 和炎症，NF-kB也是缺氧反应的关键调节因子。除了研究 IKK活性的调节缺氧，我们将进行研究，应澄清病理生理 这些发现在控制先天免疫和肿瘤引起的炎症中的重要性。另一 一个意想不到的发现是IKKg（NEMO），IKK调节亚基，参与JNK的激活 和p38 MAPK途径在B细胞中通过CD 40或BAFF受体（BAFF-R）刺激。我们会研究 IKKg通过形成信号复合物来控制这些通路的激活的机制 包括TRAF 2和MEKK 1，它们是E3泛素连接酶，以及UBC 13，一种E2泛素缀合酶， 酵素此外，我们将继续研究TRAF 2及其相关TRAF 3在控制肿瘤细胞凋亡中的作用。 响应于CD 40的参与而激活IKKa依赖性替代性NF-κ B信号传导途径， RANK、BAFF-R和光敏素（LT）a：B受体（LTbR）。我们将重点讨论TRAF 2和TRAF 3在以下方面的作用： 控制NIK的周转，NIK是一种负责IKKa活化的蛋白激酶。第三个意外发现是， 将跟进的是激活核IKKa在转录调控中的作用，这与其在转录调控中的作用无关。 在经典和替代性NF-κ B信号传导途径的调节中的已知功能。虽然我们 我们首先发现核IKKa在前列腺癌中的这种新功能，我们将通过以下方法研究其与信号传导的相关性： IKKa激活受体存在于次级淋巴器官，如脾脏， 发育和功能是IKKa依赖的。和以前一样，这些研究将促进我们的基本 IKK信号传导的理解，以及其多样性和广泛的病理生理功能。

This is an application for continuation of a 10 year old project whose goal is to understand the regulation and function of different signaling responses controlled by the IkB kinase (IKK) complex and its three subunits: IKKa, IKKb and IKKg. Progress during the previous project period has been considerable ¿ in addition to improved understanding of IKK regulation and its role in NF-kB activation, we have elucidated the roles of the two IKK catalytic subunits (IKKa and IKKb) in the control of innate immunity and inflammation as well as programmed cell death, cancer, chronic inflammatory disorders and autoimmunity. During the course of these studies, we made several unanticipated and rather surprising findings that we plan to pursue in greater detail during the next project period. These findings include the identification of the Hif1a gene, which encodes the hypoxia regulated HIF-1a subunit of the HIF-1 transcription factor, as an IKKb and NF-kB regulated gene. These results suggest that in addition to its key role in suppression of apoptosis and activation of host defense and inflammation, NF-kB is also a critical regulator of the hypoxic response. In addition to studying the regulation of IKK activity by hypoxia we will conduct studies that should clarify the pathophysiological importance of these findings in the control of innate immunity and tumor-elicited inflammation. Another unanticipated finding is the involvement of IKKg(NEMO), the IKK regulatory subunit, in activation of the JNK and p38 MAPK pathways in B cells stimulated via CD40 or BAFF receptor (BAFF-R). We will study the mechanism by which IKKg controls the activation of these pathways through formation of a signaling complex that includes TRAF2 and MEKK1, which are E3 ubiquitin ligases, and UBC13, an E2 ubiquitin conjugating enzyme. In addition we will continue to study the role of TRAF2 and its relative TRAF3 in controlling the activation of the IKKa-dependent alternative NF-kB signaling pathway in response to engagement of CD40, RANK, BAFF-R and lymphotoxin(LT)a:b receptor (LTbR). We will focus on the role of TRAF2 and TRAF3 in controlling the turnover of NIK, a protein kinase responsible for IKKa activation. A third unexpected finding that will be followed up on is a role for activated nuclear IKKa in transcriptional regulation that is not related to its already known functions in regulation of the classical and alternative NF-kB signaling pathways. Although we first found this novel function of nuclear IKKa in prostate cancer we will study its relevance to signaling by IKKa-activating receptors in cell types present within secondary lymphoid organs, such as the spleen, whose development and function are IKKa-dependent. As before these studies will advance both our basic understanding of IKK signaling as well as its varied and wide-reaching pathophysiological functions.