PATHOGENESIS AND EVOLUTION OF HUMAN T CELL LEUKEMIA/LYMPHOTROPIC VIRUSES

人类 T 细胞白血病/淋巴细胞病毒的发病机制和进化

• 批准号: 5201529
• 负责人: G FRANCHINI
• 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/5201529
• 关键词: T lymphocyte; biochemical evolution; cell cycle; cell transformation; cytokine receptors; genetic mapping; genome; growth factor receptors; human T cell leukemia; human T cell lymphotropic virus type 1; human T cell lymphotropic virus type 2; human tissue; interleukin 2; ligands; molecular pathology; nucleic acid sequence; protein sequence; receptor binding; receptor expression; tumor suppressor genes; virus genetics; virus protein

Some of the steps involved in the mechanism of T-cell transformation by human T-cell leukemia/lymphotropic virus (HTLV)-I and HTLV-II are becoming understood. Investigation of the proteins encoded by the 3' end of the HTLV-I and HTLV-II genome revealed important differences. HTLV-I encodes a protein of 12 kilodalton which carries at least four putative SH3 binding domains and behaves as a weak oncogene in mouse fibroblast. P12(I) interacts with the interleukin 2 receptor (IL-2R) beta and gamma but not alpha chains. In the presence of p12(I), downregulation of the cell surface expression of the IL-2R beta chain occurs. Preliminary data suggest that the amino terminal region of p12(I), which contains one of the SH3 binding domains, is involved in this event. Mapping of the IL-2R and p12(I) genetic determinant involved in this interaction is ongoing. A protein equivalent to p12 in HTLV-II has not been identified. However, it appears that in HTLV-I- and HTLV-II-transformed T-cells, different pathways, both leading to T-cell growth, might be activated. In HTLV-I, IL-2 independent T-cells, the JAK/STAT pathway is constitutively activated. However, this is not the case in HTLV-II IL-2 independent T-cells. Studies on the SHC-GRAB-2, MAPK pathway in HTLV- transformed cells is now underway. In both HTLV-I- and HTLV-II-transformed T-cell, alteration of cell cycle inhibitors like the p21(waf/cip1) and p53 gene appears to occur frequently. The consequence of these alterations on the Rb and Abelson proteins are also being investigated. A new simian T-cell leukemia/lymphotropic virus type I, isolated last year, has been cloned and its DNA sequence obtained. The putative amino acid sequence will be used to generate reagents that may uncover other related retroviruses in humans.

T细胞转化机制中涉及的一些步骤 人类T细胞白血病/淋巴细胞白血病病毒(HTLV)-I和HTLV-II是 变得被理解。3‘端编码蛋白质的研究 HTLV-I和HTLV-II基因组的差异显示出重要的差异。HTLV-I 编码一种12千道尔顿的蛋白质，它至少携带4个推定的 SH3结合结构域，在小鼠成纤维细胞中表现为弱癌基因。 P12(I)与白介素2受体(IL-2R)β和γ相互作用 但不是阿尔法链。在p12(I)存在的情况下，下调 细胞表面表达IL-2Rβ链。初步数据 建议p12(I)的氨基末端区域，它包含一个 SH3结合结构域参与了这一事件。白介素2受体的定位 和p12(I)参与这种相互作用的遗传决定因素正在进行中。 尚未鉴定出与HTLV-II中的p12等同的蛋白质。然而， 在HTLV-I和HTLV-II转化的T细胞中，似乎不同 这两个导致T细胞生长的途径可能会被激活。在HTLV-I中， IL-2依赖的T细胞，JAK/STAT通路是结构性的 激活了。然而，这不是HTLV-II IL-2独立的情况 T细胞。HTLV转化过程中SHC-GRAB-2、MAPK通路的研究 细胞现在正在进行中。在HTLV-I和HTLV-II转化的T细胞中， 细胞周期抑制因子p21(WAF/cip1)和P53基因的变化 似乎经常发生。这些变化的后果是 Rb和Abelson蛋白也在接受研究。 一种新的猴T细胞白血病/嗜淋巴病毒I型，LAST分离 已被克隆，并获得了其DNA序列。推定的氨基 酸序列将被用来产生可能发现其他 人类体内的相关逆转录病毒。