Mechanisms of Cellular Transformation by HTLV-1 TAX

HTLV-1 TAX 的细胞转化机制

• 批准号: 7213356
• 负责人: SUSAN J MARRIOTT
• 金额: $ 26.83万
• 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 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7213356
• 关键词: Adult; Affect; Animal Model; Biological Models; Biology; Bypass; CD4 Positive T Lymphocytes; Cell Cycle Checkpoint; Cell Cycle Progression; Cell Line; Cell Proliferation; Cell physiology; Cells; Cultured Cells; DNA Damage; DNA Repair; DNA Repair Inhibition; DNA Replication Damage; DNA biosynthesis; DNA chemical synthesis; DNA lesion; Data; Defect; Development; Doctor of Philosophy; Environment; Event; Frequencies; G1 Phase; Gene Mutation; Genome; Genome Stability; Genomic Instability; Genomics; Goals; Human T-Cell Leukemia Viruses; Human T-lymphotropic virus 1; Knowledge; Lymphocyte; Maintenance; Malignant Neoplasms; Mediating; Modeling; Molecular; Mutation; Oncogene Proteins; PCNA gene; Pathway interactions; Patients; Phase; Phenotype; Polymerase; Process; Regulator Genes; Replication Origin; Signal Pathway; T-Cell Leukemia; TP53 gene; Taxes; Testing; cell growth; experience; genetic regulatory protein; insight; metaplastic cell transformation; repaired; sample fixation; tumorigenesis

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）是成人T细胞白血病（ATL）的病原，ATL是CD4+ T细胞的侵袭性克隆恶性肿瘤。HTLV-I编码一种调节蛋白Tax，负责HTLV-I的转化潜能。虽然确切的机制尚不清楚，但税收转化取决于其激活细胞生长调节基因和调节细胞信号通路的能力。我们最近证明，Tax刺激细胞周期进入G1期，抑制DNA修复，并干扰DNA损伤诱导的G1/S检查点。这些功能允许表达税收的细胞进入S期，并在DNA修复完成之前启动DNA复制，创造一个促进DNA突变固定到宿主基因组的环境。从ATL患者中分离的转化淋巴细胞以及表达Tax的细胞系显示出与这种活性一致的各种基因组异常。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，将通过本更新应用程序进一步研究。这些研究的总体假设是，表达tax的细胞无法维持G1/S DNA损伤诱导的检查点，从而增加了细胞突变频率，增强了细胞转化的潜力。该应用程序的具体目的是：(1)确定Tax允许绕过G1/S DNA损伤诱导的细胞周期检查点的机制。(2)确定存在DNA损伤时S相进入的后果。(3)确定Tax对突变频率和细胞转化的影响。这些研究结果将定义HTLV-I转化具体过程中的关键步骤，并可能为细胞增殖和转化机制提供更广泛的见解。