CD40 SIGNALING THROUGH TNF RECEPTOR ASSOCIATED FACTORS

通过 TNF 受体相关因子进行 CD40 信号传导

• 批准号: 6326731
• 负责人: GENHONG CHENG
• 金额: $ 9.23万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-02-01 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6326731
• 关键词: CD40 molecule; biological signal transduction; cytokine; flow cytometry; gel mobility shift assay; gene expression; growth factor receptors; immunoprecipitation; northern blottings; nuclear factor kappa beta; oligonucleotides; polymerase chain reaction; protein kinase; protein purification; protein structure function; receptor binding; site directed mutagenesis; tissue /cell culture; tumor necrosis factor alpha; western blottings; yeast two hybrid system

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.

肿瘤坏死因子（Tumor necrosis factor， TNF）一直被认为是一种抗癌药物