Integration of TNF Signaling in Apoptosis

描述（由申请人提供）：肿瘤坏死因子（tnf - α）调节许多生物活性，包括免疫反应、炎症和程序性细胞死亡（凋亡）。tnf - α通过激活多种细胞内信号效应器发挥作用，如caspases、NF-kappaB和c-Jun n端蛋白激酶（JNK）。虽然tnf - α诱导的细胞凋亡需要caspase的激活，但NF-kappaB的激活可抑制细胞凋亡过程。JNK在tnf - α诱导的细胞凋亡中的作用尚不清楚。利用遗传和生化方法，我们发现NF-kappaB的激活可以通过诱导一组抑制剂阻止tnf - α诱导的JNK的延长活化。抑制JNK的延长激活可抑制tnf - α诱导的细胞凋亡，提示NF-kappaB的部分抗凋亡作用是通过抑制JNK的延长激活介导的。这项工作是新颖的，因为它提供的证据将导致描述tnf - α信号如何在凋亡过程中整合的分子基础，并且应该为开发调节tnf - α诱导的细胞凋亡的新策略提供关键信息。两个假设驱动的特定目标将被追求，以确定NF-kappaB的激活阻止响应tnf - α的延长的JNK激活的机制，以及延长的JNK激活促进tnf - α诱导的细胞凋亡的机制。

DESCRIPTION (provided by applicant): The tumor necrosis factor (TNF-alpha) regulates many biological activities, including immune responses, inflammation and programmed cell death (apoptosis). TNF-alpha exerts its function by activating multiple intracellular signaling effectors, such as caspases, NF-kappaB and c-Jun N-terminal protein kinase (JNK). While caspase activation is required for TNF-alpha induced apoptosis, activation of NF-kappaB suppresses the apoptotic process. The role of JNK in TNF-alpha induced apoptosis is unclear. Using genetic and biochemical approaches, we found that activation of NF-kappaB prevents prolonged JNK activation induced by TNF-alpha through induction of a group of inhibitors. Inhibition of prolonged JNK activation suppresses TNF-alpha induced apoptosis, suggesting that part of the anti-apoptotic effect of NF-kappaB is mediated by inhibition of prolonged JNK activation. This work is novel as it provides evidence that will lead to delineation of the molecular basis of how TNF-alpha signaling is integrated in the apoptotic process and should provide information critical to the development of novel strategies in regulation of TNF-alpha induced apoptosis. Two hypothesis-driven specific aims will be pursued to determine the mechanisms by which activation of NF-kappaB prevents prolonged JNK activation in response to TNF-alpha and the mechanism by which prolonged JNK activation contributes to TNF-alpha induced apoptosis.