HTLV-1 TAX1 AS AN EXTRACELLULAR CYTOKINE

HTLV-1 TAX1 作为细胞外细胞因子

• 批准号: 3752736
• 负责人: J BRADY
• 金额: --
• 依托单位: DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS
• 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/3752736
• 关键词: cytokine; gene expression; genetic promoter element; genetic regulation; genetic regulatory element; genetic transcription; hormone regulation /control mechanism; human T cell lymphotropic virus type 1; hypercalcemia; mutant; parathyroid hormones; tissue /cell culture; transcription factor; virus protein

Human T-cell lymphotropic virus type I (HTLV-I) is associated with two human diseases, adult T-cell leukemia (ATL) and tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM). HTLV-I Tax1 is released from infected lymphocytes and functions as an extracellular cytokine to stimulate gene expression in, and proliferation of, uninfected lymphocytes. The human parathyroid hormone related protein (PTHrP) gene has been analyzed in HTLV-I infected and uninfected cells to identify transcriptional regulatory sequences which may be a target for intracellular or extracellular Tax1. The analysis of PTHrP gene expression is important since humoral hypercalcemia of malignancy (HHM) is closely linked to PTHrP synthesis and secretion. Several types of human cancers, including ATL are frequently associated with hypercalcemia. PTHrP shares with the parathyroid hormone (PTH) the ability to interact with the PTH/PTHrP receptor and, consequently, to induce bone absorption and increased calcium reabsorption in the kidney, which eventually results in an increased calcium level in the blood. The PTHrP promoter is stimulated by several extracellular cytokines and growth factors. Expression of the parathyroid hormone related protein is regulated by two distinct promoters, P1 and P2. In HTLV-I transformed lymphocytes, RNA synthesis is initiated primarily at the P2 promoter. Using deletion and site-specific point mutations, we have identified a promoter proximal sequence (-72 to -40) which is important for Tax1 transactivation. This promoter proximal element contains binding sites for both Ets1 and Sp1. Mutation of the Ets1 GGAA core motif or the Sp1 CACCC motif significantly reduces transcriptional activity of the PTHrP promoter. These biochemical studies provide important insight into PTHrP gene regulation. This information is being utilized to develop strategies to theraputically regulate PTHrP expression and the development of hypercalcemia in cancer patients.

人类T细胞嗜淋巴细胞病毒I型（HTLV-I）与两种 成人T细胞白血病（ATL）和热带痉挛性 轻瘫/HTLV-I相关脊髓病（TSP/HAM）。 HTLV-I Tax 1是 从受感染的淋巴细胞中释放出来， 细胞因子，刺激基因表达和增殖， 未感染的淋巴细胞 人甲状旁腺激素相关蛋白 在HTLV-I感染和未感染的细胞中分析了PTHrP基因 为了鉴定可能是靶的转录调节序列， 对于细胞内或细胞外Tax 1。 甲状旁腺激素受体基因分析 表达是重要的，因为恶性体液性高钙血症（HHM） 与PTHrP的合成和分泌密切相关。 几种类型的 包括ATL在内的人类癌症通常与 高钙血症 PTHrP与甲状旁腺激素（PTH）共享 与PTH/PTHrP受体相互作用的能力， 诱导骨吸收和增加肾脏中的钙重吸收， 最终导致血液中钙含量增加。 的 PTHrP启动子被几种细胞外细胞因子刺激， 生长因子 甲状旁腺激素相关蛋白的表达受两种 不同的启动子，P1和P2。 在HTLV-I转化的淋巴细胞中，RNA 合成主要在P2启动子处起始。 使用删除和 位点特异性点突变，我们已经确定了启动子近端 序列（-72至-40），其对于Tax 1反式激活是重要的。 这 启动子近端元件包含Ets 1和Sp1的结合位点。 Ets 1 GGAA核心基序或Sp1 CACCC基序的突变显著 降低PTHrP启动子的转录活性。 这些 生物化学研究为PTHrP基因调控提供了重要的见解。 这些信息正被用于制定战略， 治疗调节PTHrP表达和发展， 癌症患者的高钙血症。