Il2 Receptors--molecular Regulation

Il2受体--分子调控

• 批准号: 6541726
• 负责人: Warren J Leonard
• 金额: --
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6541726
• 关键词: T lymphocyte; biological signal transduction; cellular immunity; cytokine receptors; gene targeting; genetic regulation; genetically modified animals; human tissue; interleukin 2; laboratory mouse; leukocyte activation /transformation; neoplasm /cancer immunology; protein structure function; receptor expression; tissue /cell culture; transcription factor

The human interleukin-2 receptor is being studied to understand critical components of the T cell immune response in normal and neoplastic cells. Following T-cell activation, IL-2 and IL-2 receptors are induced; the magnitude and duration of the T-cell immune response is controlled by the amount of IL-2 produced, the levels of receptors expressed, and the time course of these events. Three chains of the IL-2 receptor exist, IL-2Ra, IL-2Rb, and gc, with IL-2Ra and IL-2Rb being significantly regulated at the level of transcription. The group has focused primarily on the types of signals induced by IL-2, particularly the activation of STAT proteins (signal transducers and activators of transcription), and the mechanism by which they regulate the IL-2Ra gene. Stat5a and Stat5b are two closely related proteins with >90% amino acid identity that are activated by IL-2. An issue is whether these closely related proteins are redundant or distinctive in their actions. To attempt to clarify this issue, Stat5a and Stat5b transgenic mice have been generated to reconstitute the knockout mice. Moreover, in addition to a previously reported IL-2 response element in the 5' regulatory region of the IL-2Ra gene, the existence of another important regulatory element, denoted PRRIV, was reported. This element is highly conserved in humans and mice and is located in the first intron. This element is regulated by Stat5 and HMG-I(Y) proteins. Together with the upstream IL-2 response element, the intronic element controls IL-2-mediated regulation of the IL-2Ra gene. In a collaborative study, it was also reported that the HTLV-1 p12I protein can enhance Stat5 activation and diminish the IL-2 requirement for proliferation of primary human peripheral blood mononuclear cells. Together, these studies substantially enhance our understanding of the basis of IL-2R expression and Stat5-dependent gene regulation.

人们正在研究人类白介素2受体，以了解正常细胞和肿瘤细胞中T细胞免疫反应的关键成分。T细胞激活后，IL-2和IL-2受体被诱导；T细胞免疫反应的大小和持续时间由IL-2的生成量、受体的表达水平和这些事件的时间进程控制。IL-2受体存在三条链，即IL-2Ra、IL-2Rb和GC，其中IL-2Ra和IL-2Rb在转录水平上受到显著调控。该小组主要关注IL-2诱导的信号类型，特别是STAT蛋白(信号转导和转录激活剂)的激活，以及它们调节IL-2ra基因的机制。Stat5a和Stat5b是两个密切相关的蛋白质，它们被IL-2激活，具有90%的氨基酸同源性。一个问题是，这些密切相关的蛋白质在它们的作用中是多余的还是独特的。为了澄清这个问题，已经产生了Stat5a和Stat5b转基因小鼠来重建基因敲除小鼠。此外，除了先前报道的IL-2Ra基因5‘调控区的一个IL-2反应元件外，还有另一个重要的调节元件的存在，被称为PRRIV。该元件在人类和小鼠中高度保守，位于第一内含子。该元件受Stat5和HMG-I(Y)蛋白的调节。内含子元件与上游的IL-2反应元件一起控制IL-2对IL-2ra基因的调节。在一项合作研究中，也有报道HTLV-1 p12I蛋白可以增强Stat5的激活，并降低原代培养的人外周血单个核细胞增殖所需的IL-2。总之，这些研究大大加强了我们对IL-2R表达和Stat5依赖的基因调控的基础的理解。