Regulation of Cellular Response to TNF

描述(申请人提供)：肿瘤坏死因子(肿瘤坏死因子或肿瘤坏死因子)是建立和维持多种炎症性和自身免疫性疾病的关键介质，如类风湿性关节炎和炎症性肠病。肿瘤坏死因子受体信号通路可以同时激活转录因子caspase8、核因子-kappaB和蛋白激酶JNK。虽然caspase8的激活是肿瘤坏死因子诱导的细胞凋亡所必需的，而核因子-kappaB的诱导抑制了细胞死亡，但JNK激活在肿瘤坏死因子信号转导中的确切作用尚不清楚。我们已经证明，肿瘤坏死因子介导的caspase8的裂解和凋亡需要一条涉及JNK、BID和Smac/Diablo的顺序通路。JNK的激活诱导不依赖于caspase 8的BID在不同的位点切割，产生BID切割产物jBid。JBid易位到线粒体导致Smac/Diablo优先释放，而不是细胞色素c。释放的Smac/DIABLO随后破坏TRAF2-CIAP 1复合体。我们认为，JNK途径是必需的，以解除TRAF2-cIAP1对caspase 8激活和诱导细胞凋亡的抑制。在这个提案中，我们将探索在肿瘤坏死因子反应中选择细胞存活和细胞死亡的信号机制。由于肿瘤坏死因子介导的细胞凋亡在肿瘤坏死因子的生理和病理生理功能中都起着至关重要的作用，了解肿瘤坏死因子反应的调节将为肿瘤坏死因子介导的炎症性和自身免疫性疾病的治疗干预提供新的途径。

DESCRIPTION (provided by applicant): Tumor necrosis factor (TNF or TNFalpha) is a key mediator in the establishment and maintenance of multiple inflammatory and autoimmune diseases, such as rheumatoid arthritis and inflammatory bowel disease. TNF receptor signaling can simultaneously activate caspase 8, the transcription factor, NF-KappaB and the kinase, JNK. While activation of caspase 8 is required for TNF-induced apoptosis, and induction of NF-KappaB 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 of jBid 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 autoimmune diseases.