Tumor Necrosis Factor Action in Cells

肿瘤坏死因子（TNF）是一种具有治疗癌症潜力的细胞因子，它还能促进免疫、伴随疾病状态的代谢变化、胰岛素抵抗、炎症、血管生成和伤口愈合。为了实现TNF作为治疗剂的潜力，减弱其病理活性并促进其有益作用，需要深入了解TNF的工作原理。TNF作用的第一步是与两个受体中的任何一个结合。1型TNF受体（TNFR1）促进恶性肿瘤细胞凋亡、成纤维细胞增殖、抗病毒反应、一组转录因子的激活，并在宿主防御微生物中发挥主导作用。出于这个原因，本提案侧重于TNFR1如何介导其作用。最近的工作主要集中在TNFR1与一组含有死亡结构域基序的细胞内蛋白的关联以及这些蛋白在TNF作用中的作用。我的实验室发现，TNFR1信号复合体由比以前认识到的更多的蛋白质组成。我们发现TNFR1复合体包含Jak激酶、c-Src（一种非受体酪氨酸激酶）、SHP-1（一种蛋白酪氨酸磷酸酶）、磷脂酰肌醇3-激酶（一种脂质激酶）和Rac1（一种GTPase）。这些新发现的TNFR1复合物组分在NF-kappaB的激活中发挥作用，NF-kappaB是一种对免疫和细胞存活很重要的转录因子。Rac1可能在耦合TNFR1激活p38 MAPK和JNK激酶中发挥作用，激活对应激反应重要的转录因子。本提案的目的是确定TNFR1复合体如何形成并偶联到产生TNF反应的途径，以及该复合体如何决定细胞的存活或死亡。

Tumor necrosis factor (TNF) is a cytokine with the potential for the treatment of cancer that also promotes immunity, metabolic changes that accompany disease states, insulin resistance, inflammation, angiogenesis and wound healing. To realize the potential of TNF as a therapeutic agent, to attenuate its pathological activities and promote its beneficial effects requires insight into how TNF works. The first step in TNF action is binding to either of two receptors. The type 1 TNF receptor (TNFR1) promotes apoptosis in malignancies, fibroblast proliferation, antiviral responses, activation of a group of transcription factors, and plays a predominant role in the host defense against microorganisms. For this reason, this proposal focuses on how TNFR1 mediates its effects. Most recent work has focused on association of TNFR1 with a group of intracellular proteins that contain a death domain motif and the role of these proteins in TNF action. My laboratory has found that the TNFR1 signaling complex is composed of more proteins than previously appreciated. We have found that the TNFR1 complex contains Jak kinase, c-Src, a non-receptor tyrosine kinase, SHP-1, a protein tyrosine phosphatase, phosphatidylinositol 3-kinase, a lipid kinase, and Rac1, a GTPase. These newly identified components of the TNFR1 complex play a role in activation of NF-kappaB, a transcription factor important to immunity and cell survival. It is likely that Rac1 plays a role in coupling TNFR1 to activate p38 MAPK and JNK kinases that activate transcription factors important to stress responses. The aims of this proposal are to determine how the TNFR1 complex forms and couples to pathways that generate TNF responses and how the complex determines whether cells live or die.