Regulation of NF-kapaB and IKK by proinflammatory stimuli

促炎刺激对 NF-kapaB 和 IKK 的调节

• 批准号: 8067522
• 负责人: Michael Karin
• 金额: $ 5.82万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8067522
• 关键词: 10 year old; Antibody Activation; Apoptosis; Autoimmunity; B-Lymphocytes; Biological Process; Catalytic Domain; Cell Nucleus; Cell Survival; Cells; Chronic; Complex; Development; Disease; Family member; Fibroblasts; Gene Targeting; Genes; Genetic Transcription; Goals; Host Defense; Hypoxia; Immunity; Infection; Inflammation; Inflammatory; Inflammatory Response; Link; Lymphoid; Lysine; MAP Kinase Gene; MAP3K1 gene; MAPK14 gene; MAPK8 gene; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metastasis Suppressor Genes; Modification; Myeloid Cells; NF-kappa B; NF-kappaB-inducing kinase; NFKB Signaling Pathway; Natural Immunity; Necrosis; Nuclear; Organ; Pathogenesis; Pathway interactions; Phosphotransferases; Prevention; Protein Kinase; Receptor Activation; Receptor Signaling; Regulation; Relative (related person); Repression; Role; Signal Pathway; Signal Transduction; Spleen; Stimulus; Subgroup; TNF receptor-associated factor 3; TNFRSF5 gene; TRAF2 gene; TRANCE protein; Testing; Transcriptional Regulation; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-Beta; Ubiquitin; Ubiquitin-Conjugating Enzymes; Ubiquitination; antimicrobial; cell type; follow-up; improved; macrophage; maspin; microbial; novel; receptor; response; transcription factor; tumor; tumor progression; ubiquitin-protein ligase

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.

这是一个延续了10年的项目的申请，其目标是了解 IKB激酶(IKK)复合体及其受体控制的不同信号反应的调控和功能 三个亚单位：IKKA、IKKB和IKKg。在前一个项目期内取得了相当大的进展 除了对IKK调节及其在核因子-kB激活中的作用有了更好的理解外，我们还阐明了 两个IKK催化亚基(IKKA和IKKB)在控制先天免疫和炎症中的作用 以及程序性细胞死亡、癌症、慢性炎症性疾病和自身免疫。在…的过程中 在这些研究中，我们得出了几个出人意料的发现，我们计划在更大的范围内继续研究 在下一个项目期间提供详细信息。这些发现包括HIF1a基因的鉴定，该基因编码 低氧调控HIF-1转录因子HIF-1a亚单位，作为IKKB和NF-kB调控基因。 这些结果表明，除了在抑制细胞凋亡和激活宿主防御方面发挥关键作用外， 而炎症方面，核因子-kB也是低氧反应的关键调节因子。除了研究 低氧对IKK活性的调节我们将进行研究，以澄清病理生理学。 这些发现在控制先天免疫和肿瘤引起的炎症方面的重要性。另一个 意想不到的发现是IKK调节亚基IKKg(Nemo)参与了JNK的激活 CD40或BAFF受体(BAFF-R)刺激的B细胞p38MAPK通路。我们会研究 IKKg通过形成信号复合体来控制这些通路的激活的机制 这包括TRAF2和MEKK1，它们是E3泛素连接酶，以及UBC13，E2泛素结合 酵素。此外，我们将继续研究TRAF2及其相关的TRAF3在控制 CD40激活依赖于Ikka的替代核因子-kB信号通路， RANK、BAFF-R和淋巴毒素(LT)a：B受体(LTbR)。我们将重点介绍TRAF2和TRAF3在 控制Nik的周转，Nik是一种负责Ikka激活的蛋白激酶。第三个意外的发现是 将被跟踪的是激活的核Ikka在转录调控中的作用，这与其无关 已知的功能调节经典的和替代的核因子-kB信号通路。虽然我们 首次发现核Ikka在前列腺癌中的这一新功能，我们将通过以下方式研究其与信号的相关性 次级淋巴器官中存在的细胞类型中的IKKA激活受体，如脾，其 发展和功能依赖于Ikka。一如既往，这些研究将推动我们的基本 了解ikk信号及其多样而广泛的病理生理功能。