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Regulation of Cellular Response to TNF

细胞对 TNF 反应的调节

基本信息

批准号：
7325762
负责人：
Xiangwei Wu
金额：
$ 27.91万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-12-15 至 2009-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7325762
关键词：
Address Affect Apoptosis Apoptotic Binding Biological Assay Cardiolipins Cell Death Cell Survival Cessation of life Cleaved cell Complex Dimerization Disease Endopeptidases Fractionation Generations High Pressure Liquid Chromatography In Vitro Induction of Apoptosis Inflammatory JNK-activating protein kinase Lipids MAPK8 gene Maintenance Mediating Mediator of activation protein Mitochondria Pathway interactions Peptide Hydrolases Permeability Physiological Play Protein Family Proteins Reaction Receptor Signaling Recruitment Activity Regulation Rheumatoid Arthritis Role Signal Pathway Signal Transduction Site System TNF Receptor-Associated Death Domain Protein TNF gene TNF receptor-associated factor 2 TRADD gene TRAF2 gene Testing Therapeutic Intervention Tumor Necrosis Factor Receptor Tumor Necrosis Factor-alpha Tumor Necrosis Factors base caspase-8 cell growth regulation cytochrome c human TNF protein in vivo member mutant novel pro-caspase-8 receptor response transcription factor

项目摘要

Tumor necrosis factor (TNF or TNFcz) is a key mediator in the establishment and maintenance of multiple inflammatory and autoimmue diseases, such as rheumatoid arthritis and inflammatory bowl disease. TNF- receptor signaling can simultaneously activate caspase 8, the transcription factor, NF-KB and the kinase, JNK. While activation of caspase 8 is required for TNF-induced apoptosis, and induction of NF-rd3 inhibits cell death, the precise function of JNK activation in TNF signaling is not clearly understood. We have shown that TNF-mediated caspase 8 cleavage and apoptosis require a sequential pathway involving JNK, Bid, and Smac/DIABLO. Activation of JNK induces caspase 8-independent cleavage of Bid at a distinct site to generate the Bid cleavage product jBid. Translocation ofjBid to mitochondria leads to preferential release of Smac/DIABLO, but not cytochrome c. The released Smac/DIABLO then disrupts the TRAF2-cIAP 1 complex. We propose that the JNK pathway is required to relieve the inhibition imposed by TRAF2-cIAP1 on caspase 8 activation and induction of apoptosis. In this proposal, we will explore the signaling mechanisms underlying the choice between cell survival and cell death in TNF response. Since TNF- mediated apoptosis plays a crucial role in both physiological and pathophysiological functions of TNF, understanding the regulation of TNF response will provide new avenues of therapeutic intervention for TNF- mediated inflammatory and autoimmue diseases.

肿瘤坏死因子（TNF或TNFcz）是建立和维持多个肿瘤细胞的关键介质。炎性和自身免疫性疾病，如类风湿性关节炎和炎性肠病。肿瘤坏死因子受体信号传导可以同时激活半胱天冬酶8、转录因子NF-κ B和激酶JNK。 TNF诱导的细胞凋亡需要caspase 8的激活，而NF-rd 3的诱导抑制了细胞凋亡。死亡，JNK活化在TNF信号传导中的确切功能尚不清楚。我们已经证明 TNF介导的caspase 8裂解和凋亡需要一个涉及JNK、Bid和 Smac/DIABLO。JNK的激活诱导Bid在不同位点的半胱天冬酶8非依赖性切割，生成Bid拆分产品jBid。将jBid转运至线粒体导致优先释放 Smac/DIABLO，但不是细胞色素c。然后释放的Smac/DIABLO破坏TRAF 2-cIAP 1，复杂.我们认为JNK通路是解除TRAF 2-cIAP 1抑制所必需的。对caspase 8活化和诱导凋亡的影响。在本提案中，我们将探讨 TNF应答中细胞存活和细胞死亡之间选择的潜在机制。由于TNF- 介导的细胞凋亡在TNF的生理和病理生理功能中起着至关重要的作用，了解TNF反应的调节将为TNF的治疗干预提供新的途径，介导的炎症和自身免疫性疾病。