Mechanisms of Cellular Transformation by HTLV-1 TAX

HTLV-1 TAX 的细胞转化机制

• 批准号: 6687008
• 负责人: SUSAN J MARRIOTT
• 金额: $ 28.29万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6687008
• 关键词: DNA damage; DNA repair; DNA replication; cell cycle; cell transformation; gene expression; gene mutation; human T cell lymphotropic virus type 1; immunoprecipitation; laboratory mouse; oncoproteins; proliferating cell nuclear antigen; tissue /cell culture; transcription factor; virus protein; western blottings; DNA damage; DNA repair; DNA replication; cell cycle; cell transformation; gene expression; gene mutation; human T cell lymphotropic virus type 1; immunoprecipitation; laboratory mouse; oncoproteins; proliferating cell nuclear antigen; tissue /cell culture; transcription factor; virus protein; western blottings

DESCRIPTION (provided by applicant): Human T-cell leukemia virus type I (HTLV-I) is the etiologic agent of adult T cell leukemia (ATL), an aggressive clonal malignancy of CD4+ T cells. HTLV-I encodes a regulatory protein, Tax, which is responsible for the transforming potential of HTLV-I. Although the precise mechanism remains unknown, Tax transformation depends upon its ability to activate cellular growth regulatory genes, and to modulate cellular signaling pathways. We have recently demonstrated that Tax stimulates cell cycle progression through G1 phase, suppresses DNA repair, and interferes with the DNA damage-induced G1/S checkpoint. These functions allow Tax-expressing cells to enter S phase and initiate DNA replication prior to the completion of DNA repair, creating an environment that promotes the fixation of DNA mutations into the host genome. Transformed lymphocytes isolated from ATL patients as well as Tax expressing cell lines display a variety of genomic abnormalities that are consistent with this activity. Together, these observations provide an intriguing model for Tax-mediated transformation, which will be further investigated through this renewal application. The overall hypothesis for these studies is that Tax-expressing cells fail to maintain the G1/S DNA damage induced checkpoint, thereby increasing the cellular mutation frequency and enhancing the potential for cellular transformation. The specific aims of this application are: (1) To determine the mechanism by which Tax allows bypass of the G1/S DNA damage induced cell cycle checkpoint. (2) To determine the consequences of S phase entry in the presence of DNA damage. (3) To determine the effect of Tax on mutation frequency and cellular transformation. The results of these studies will define critical steps in the specific process of HTLV-I transformation and are likely to provide broader insights into mechanisms of cellular proliferation and transformation.

描述（由申请人提供）：人类T细胞白血病病毒I型（HTLV-I）是成年T细胞白血病（ATL）的病因，这是CD4+ T细胞的侵略性克隆恶性肿瘤。 HTLV-I编码一种调节蛋白，税收，该蛋白质负责HTLV-I的转化潜力。尽管确切机制仍然未知，但税收转化取决于其激活细胞生长调节基因的能力，并调节细胞信号通路。我们最近证明，税收刺激细胞周期通过G1相，抑制DNA修复，并干扰DNA损伤诱导的G1/S检查点。这些功能使表达税收的细胞可以进入S相并在DNA修复完成之前启动DNA复制，从而创造了一种环境，从而促进了DNA突变固定在宿主基因组中。从ATL患者中分离出来的转化的淋巴细胞以及表达细胞系的税收表现出与该活性一致的多种基因组异常。总之，这些观察结果为税收介导的转型提供了一个有趣的模型，将通过此续签应用进一步研究。这些研究的总体假设是，表达税收的细胞无法维持G1/S DNA损伤引起的检查点，从而增加了细胞突变频率并增强了细胞转化的潜力。该应用程序的具体目的是：（1）确定税收允许绕过G1/S DNA损伤引起的细胞周期检查点的机制。 （2）确定在存在DNA损伤的情况下S相进入的后果。 （3）确定税收对突变频率和细胞转化的影响。这些研究的结果将在HTLV-I转化的特定过程中定义关键步骤，并可能提供对细胞增殖和转化机制的更广泛见解。