Regulation of TNF Receptor-Mediated Apoptosis

TNF 受体介导的细胞凋亡的调节

• 批准号: 7624483
• 负责人: ADRIAN T TING
• 金额: $ 42.38万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7624483
• 关键词: Address; Animal Model; Anti-Inflammatory Agents; Apoptosis; Apoptotic; Binding; Biology; Caspase; Cell Death; Cell Survival; Cells; Cessation of life; Development; Disease; Funding; Genes; Genetic; Genetic Transcription; Human; Inflammatory; Knock-in Mouse; Lead; Life; Link; Lysine; Mediating; Modeling; Modification; Molecular; Mus; Mutation; NF-kappa B; Pathway interactions; Play; Protein Biosynthesis; Regulation; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Site; T-Lymphocyte; TNF receptor-associated factor 2; TRAF2 gene; Testing; Therapeutic; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-alpha; Ubiquitin; Ubiquitination; cell type; cytotoxic; human TNFRSF1A protein; immune function; in vivo; insight; loss of function; novel; receptor; response; transcription factor; tumor necrosis factor alpha receptor; ubiquitin-protein ligase

TNF binding to its receptor TNFR1 triggers cell survival or cell death but the mechanisms that determine which of these two divergent responses is triggered remain to be fully elucidated. One cell death checkpoint is the activation of NF-kappaB transcription factors and subsequent induction of anti-apoptotic genes to inhibit the apoptosis pathway. Preliminary studies performed demonstrated the existence of another cell death checkpoint regulated by lysine 63-linked ubiquitination of RIP1. Ubiquitination of lysine 377 on RIP1 inhibits TNF-induced apoptosis first through an NF-kappaB-independent mechanism, and subsequently through an NF-kappaBdependent mechanism. In contrast, in the absence of ubiquitination, RIP1 serves as a proapoptotic signaling molecule. Thus, RIP1 is a dual-function molecule that can be either pro-survival or pro-death depending on its ubiquitination state and thus serves as an NFkappaB- independent cell death switch early in TNF signaling. This study proposes to examine how this cell death checkpoint may be regulated. (1) The mechanism by which ubiquitination of RIP1, or the lack of it, regulates the activation of caspases will be examined. (2) The contribution by RIP1-binding partners to this checkpoint will also be tested. (3) Animal models with genetic modifications in this novel cell death checkpoint will be developed to study the relevance of this checkpoint in immune function. Insights gained from these studies may lead to the development of pharmacological agents that can modulate this cell death checkpoint. Such agents may have therapeutic potential in inflammatory diseases where TNF plays a role.

TNF与其受体TNFR 1结合触发细胞存活或细胞死亡，但TNF受体的表达与细胞存活或细胞死亡无关。 决定这两种不同反应中哪一种被触发的机制仍然存在， 要充分阐明。一个细胞死亡检查点是NF-κ B的激活 转录因子和随后诱导抗凋亡基因以抑制细胞凋亡。 凋亡途径初步研究表明，存在另一种 细胞死亡检查点由RIP 1的赖氨酸63连接的泛素化调节。 RIP 1上赖氨酸377的泛素化首先通过抑制肿瘤坏死因子诱导的细胞凋亡， NF-κ B非依赖性机制，随后通过NF-κ B依赖性 机制相反，在没有泛素化的情况下，RIP 1作为促凋亡蛋白发挥作用。 信号分子因此，RIP 1是一种双功能分子，可以是 促生存或促死亡，这取决于其泛素化状态，因此作为NF κ B- TNF信号传导早期独立细胞死亡开关。本研究建议， 研究细胞死亡检查点是如何被调节的。(1)的机制 RIP 1的泛素化，或缺乏它，调节半胱天冬酶的激活， 考察(2)RIP 1绑定合作伙伴对此检查点的贡献也将是 测试. (3)在这种新的细胞死亡检查点中进行遗传修饰的动物模型 将被开发来研究这个检查点在免疫功能中的相关性。见解 从这些研究中获得的信息可能导致开发药理学试剂， 可以调节这个细胞死亡检查点。这些药物可能具有治疗潜力， 炎症性疾病，其中TNF发挥作用。