CD40 SIGNALING THROUGH TNF RECEPTOR ASSOCIATED FACTORS

肿瘤坏死因子（TNF）被认为是一种抗癌药物 自从二十年前被发现以来 TNF受体（TNFR） 超家族可以向细胞发送生存和死亡信号， 在广泛的生物效应中发挥重要作用，包括急性 相反应和淋巴细胞活化。 CD 40作为其中的一员 受体家族，激活多种信号通路，诱导 许多基因的表达，并且对于许多重要的 T细胞依赖性体液反应中的事件。 我们的目标是找到 可以将CD 40受体连接到多种信号传导通路的连接 信号转导通路，并将每个信号转导通路与其 下游效应基因和CD 40介导的生物学功能。 最近发现的几种早期信号介质，包括 TNF受体相关因子（TRAF）家族蛋白，TRAF- 相关NF-κ B激活剂（TANK）和NF-κ B诱导激酶 (NIK)，提供了一个机会，剖析多种CD 40介导的 信号转导途径 本提案将重点关注CD 40受体启动的 信号 首先，我们将确定多个TRAF的特异性 从CD 40接收信号并向下游发送信号的蛋白质 激活NF-κ B和应激激活蛋白的信号 激酶（SAPK）信号转导通路。第二，我们将确定 TRAF和TANK协同作用的分子机制。 我们还将 测试TANK作为开关分子在控制 CD 40诱导的NF-κ B和SAPK活化的阈值。 我们的工作将：1）提供新的见解的分子机制， 一个受体与其配体相互作用时 多种信号转导途径和控制多种生物 2）在多种CD 40和CD 44事件中鉴定新的治疗靶点， 用于治疗癌症和免疫疾病的TNF信号传导途径。

Tumor necrosis factor (TNF) has been considered as an anti-cancer agent since its discovery two decades ago. Members of the TNF receptor (TNFR) superfamily can send both survival and death signals to cells, and play important roles in a wide range of biological effects that include acute phase responses and lymphocyte activation. CD40, as a member of this receptor family, activates multiple signaling pathways, induces expression of dozens of genes, and is essential for many important events in T-cell-dependent humoral responses. Our goal is to find connections that can link the CD40 receptor to multiple signal transduction pathways, and that link each signaling pathway to its downstream effector genes and to the CD40-mediated biological functions. The recent discovery of several early signaling mediators, including the TNF receptor-associated factor (TRAF) family proteins, the TRAF- associated NF-kappaB activator (TANK) and the NF-kappaB-inducing kinase (NIK), has provided an opportunity to dissect multiple CD40-mediated signal transduction pathways. This proposal will focus on the early events of CD40 receptor-initiated signaling. First, we will determine the specificities of multiple TRAF proteins for receiving signals from CD40 and for sending out downstream signals to activate both the NF-kappaB and stress-activating protein kinase (SAPK) signal transduction pathways. Second, we will determine the molecular mechanisms of TRAF and TANK cooperation. We will also test the possible role of TANK as a switching molecule in controlling the threshold of CD40-induced NF-KB and SAPK activation. Our work will: 1) provide new insights into the molecular mechanisms by which a single receptor interacting with its ligand can generate multiple signal transduction pathways and control multiple biological events; and 2) identify new therapeutic targets in the multiple CD40 and TNF signaling pathways for treatment of cancers and immune diseases.