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，它还可以促进免疫、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。要实现肿瘤坏死因子作为治疗剂的潜力，减轻其病理活动并促进其有益效果，需要深入了解肿瘤坏死因子是如何发挥作用的。肿瘤坏死因子作用的第一步是与两种受体中的任何一种结合。1型肿瘤坏死因子受体(TNFR1)促进肿瘤细胞的凋亡、成纤维细胞的增殖、抗病毒反应、一组转录因子的激活，在宿主对微生物的防御中发挥着重要作用。出于这个原因，这项建议侧重于TNFR1如何调节其影响。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联系以及这些蛋白在肿瘤坏死因子作用中的作用。我的实验室发现，TNFR1信号复合体由比之前估计的更多的蛋白质组成。我们发现，TNFR1复合体含有Jak激酶、c-Src(非受体酪氨酸激酶)、SHP-1(蛋白酪氨酸磷酸酶)、磷脂酰肌醇3-激酶、脂蛋白激酶和rac1(GTP酶)。这些新发现的TNFR1复合体的成分在核因子-kappaB的激活中发挥作用，核因子-kappaB是一种对免疫和细胞生存至关重要的转录因子。Rac1很可能在偶联TNFR1以激活p38MAPK和JNK激酶的过程中发挥作用，而p38MAPK和JNK激酶激活对应激反应至关重要的转录因子。这项提议的目的是确定TNFR1复合体如何形成并连接到产生肿瘤坏死因子反应的途径，以及该复合体如何决定细胞的生存或死亡。

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.