Role of TRAF1 in signaling by TNFR2 family members

TRAF1 在 TNFR2 家族成员信号传导中的作用

• 批准号: 7169758
• 负责人: Erdyni Nikolaevich Tsitsikov
• 金额: $ 8.91万
• 依托单位: IMMUNE DISEASE INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7169758
• 关键词: B lymphocyte; Epstein Barr virus; T lymphocyte; biological signal transduction; cytokine receptors; differentiation antigens; genetically modified animals; laboratory mouse; lymphoma; neoplastic transformation; tumor necrosis factor alpha; virus protein

DESCRIPTION (provided by applicant): Tumor Necrosis Factor (TNF) and it homologues play important roles in a wide array of biological processes including the acute phase response, cell growth and apoptosis, inflammation and lymphocyte activation. TNF has two receptors: TNFR1and TNFR2. TNFR2 represent a family of transmembrane proteins with intracellular region, which lack a death domain. Each of TNFR2 family receptors may associate with one or several TRAF signal transduction molecules. TRAF2, TRAF3, TRAF5, and TRAF6 were shown to participate in signal transduction and activation of NF-kappaB and AP-1 transcription factors. Little is known about TRAF1 function except it is predominantly expressed in activated lymphocytes and is associated with a number of distinct members of the TNFR family, including TNFR2, CD27, CD30, 4-1BB, OX-40, HVEM, TRANCE-R, XEDAR, AITR and others. TRAF1 also binds to latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV). To elucidate the function of TRAF 1 we have generated TRAF 1-deficient mice. Compared to wild type T cells, TRAF1-deficient T cells exhibit markedly increased proliferation to anti-CD3 stimulation. Activated T cells from TRAF1-deficient mice, but not from their normal littermates, responded to TNF by proliferation and activation of NF-kappaB and AP-1. Furthermore, skin from TRAF1-deficient mice was hypersensitive to TNF-induced T-cell mediated necrosis. Taken together, these findings suggest that TRAF1 is a negative regulator of TNF signaling. We propose to apply state of the art knowledge and techniques to further understand TRAF1 function in T and B lymphocytes. We plan to address three important questions: 1. What is the precise biochemical mechanism of TRAF1 negative regulation of TNFR2 signaling? We will study the molecular mechanism of inhibition of TNFR2 signaling by TRAF1. We will determine the role of TRAF1 in signal transduction by TNFR2 in the absence of TNFR1 and signal transduction by TNFR1 in the absence of TNFR2. For this purpose we will breed TRAF1-deficient mice with mice deficient in TNFR1 or TNFR2.2. TRAF1 might have similar function for other members of TNFR2 family expressed on T cells, including OX40, 4- 1bb, CD30, and CD27. Then again, TRAF1-/- mice, in opposite to OX40-/- mice, were hyperresponsive in a model of allergic asthma. We propose to determine the role of TRAF1 in OX40 signaling in vitro and in vivo.3. What is the role of TRAF1 in signaling by EBV LMP1? We will analyze the role of TRAF1 in EBV LMP1 signaling and B cell.

描述（由申请人提供）：肿瘤坏死因子（TNF）及其同源物在一系列广泛的生物学过程中发挥重要作用，包括急性期反应，细胞生长和凋亡，炎症和淋巴细胞活化。TNF有两种受体：tnfr1和TNFR2。TNFR2是一个具有胞内区域的跨膜蛋白家族，缺乏死亡结构域。TNFR2家族的每一个受体都可能与一个或几个TRAF信号转导分子相关联。TRAF2、TRAF3、TRAF5和TRAF6参与NF-kappaB和AP-1转录因子的信号转导和激活。TRAF1主要在活化淋巴细胞中表达，并与TNFR家族的许多不同成员相关，包括TNFR2、CD27、CD30、4-1BB、OX-40、HVEM、TRANCE-R、XEDAR、AITR等，对其功能知之甚少。TRAF1还能结合eb病毒（EBV）的潜伏膜蛋白1 （LMP1）。为了阐明TRAF - 1的功能，我们制造了TRAF - 1缺陷小鼠。与野生型T细胞相比，traf1缺陷T细胞在抗cd3刺激下增殖明显增加。来自traf1缺陷小鼠的活化T细胞通过NF-kappaB和AP-1的增殖和活化对TNF作出反应，而不是来自正常窝鼠的活化T细胞。此外，traf1缺陷小鼠的皮肤对tnf诱导的t细胞介导的坏死非常敏感。综上所述，这些发现表明TRAF1是TNF信号的负调节因子。我们建议运用最新的知识和技术来进一步了解TRAF1在T淋巴细胞和B淋巴细胞中的功能。我们计划解决三个重要问题：