CD40 SIGNALING THROUGH TNF RECEPTOR ASSOCIATED FACTORS

肿瘤坏死因子被认为是一种抗癌药物。 自从二十年前它被发现以来。肿瘤坏死因子受体(TNFR)成员 超级家族可以向细胞发送生存和死亡信号，并发挥作用 在广泛的生物效应中发挥重要作用，包括急性 时相反应和淋巴细胞活化。CD40，作为这个组织的一员 受体家族，激活多个信号通路，诱导 几十个基因的表达，对许多重要的 T细胞依赖的体液反应中的事件。我们的目标是找到 可将CD40受体与多种信号联系起来的连接 转导通路，并将每条信号通路连接到其 下游的效应基因和CD40介导的生物学功能。 最近发现了几个早期的信号调节器，包括 肿瘤坏死因子受体相关因子(TRAF)家族蛋白，TRAF- 相关的核因子-kappaB激活物(TANK)与核因子-kappaB诱导的激酶 (NIK)，提供了一个机会来剖析CD40介导的多个 信号转导通路。 这项建议将聚焦于CD40受体启动的早期事件 发信号。首先，我们将确定多个TRAF的特殊性 从CD40接收信号和向下游发送信号的蛋白质 激活核因子-kappaB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和坦克协同作战的分子机制。我们还将 测试TANK作为开关分子在控制中的可能作用 CD40诱导的核因子-KB和SAPK激活阈值。 我们的工作将：1)通过以下方式为分子机制提供新的见解 单个受体与其配体相互作用可以产生 多条信号转导途径与控制多个生物 事件；以及2)在多个CD40和 肿瘤坏死因子信号通路在癌症和免疫疾病治疗中的作用。

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.