Integration of TNF Signaling in Apoptosis

描述(申请人提供)：肿瘤坏死因子(肿瘤坏死因子-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(细胞凋亡)。肿瘤坏死因子-α通过激活多种细胞内信号效应因子，如半胱氨酸氨基转移酶、核因子-kappaB和c-jun氨基末端蛋白激酶等发挥作用。而caspase的激活是肿瘤坏死因子-α诱导的细胞凋亡所必需的，而核因子-kappaB的激活则抑制了细胞的凋亡过程。JNK在肿瘤坏死因子-α诱导的细胞凋亡中的作用尚不清楚。利用遗传学和生物化学方法，我们发现，核因子-kappaB的激活通过诱导一组抑制剂来阻止由肿瘤坏死因子-α诱导的JNK的延长激活。抑制延长的JNK活化可抑制肿瘤坏死因子-α诱导的细胞凋亡，提示核因子-kappaB的部分抗凋亡作用是通过抑制延长的JNK活化来实现的。这项工作是新颖的，因为它提供了证据，将导致描绘肿瘤坏死因子-α信号如何整合到凋亡过程的分子基础，并将为开发调控肿瘤坏死因子-α诱导的细胞凋亡的新策略提供关键信息。两个假说驱动的特定目标将被用来确定核因子-kappaB的激活阻止对肿瘤坏死因子-α的反应而延长的JNK激活的机制，以及延长的JNK激活促进肿瘤坏死因子-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.