Regulation of Cellular Response to TNF

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。

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.