Mechanisms of Cellular Transformation by HTLV-1 TAX

描述（由申请方提供）：人T细胞白血病病毒I型（HTLV-I）是成人T细胞白血病（ATL）的病原体，ATL是一种CD 4 + T细胞的侵袭性克隆性恶性肿瘤。HTLV-I编码调节蛋白Tax，其负责HTLV-I的转化潜力。虽然确切的机制仍然未知，但Tax转化依赖于其激活细胞生长调节基因和调节细胞信号传导途径的能力。我们最近已经证明，税收刺激细胞周期进程通过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Tax表达细胞进入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中的环境。从ATL患者分离的转化淋巴细胞以及Tax表达细胞系显示出与该活性一致的多种基因组异常。总之，这些观察结果为Tax介导的转化提供了一个有趣的模型，这将通过此次更新申请进一步研究。这些研究的总体假设是Tax表达细胞不能维持G1/S DNA损伤诱导的检查点，从而增加细胞突变频率并增强细胞转化的潜力。本申请的具体目的是：（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)确定在DNA损伤的情况下进入S期的后果。(3)确定Tax对突变频率和细胞转化的影响。这些研究的结果将定义HTLV-I转化的特定过程中的关键步骤，并可能为细胞增殖和转化机制提供更广泛的见解。

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.