Mechanisms of Cellular Transformation by HTLV-1 TAX

描述(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)的病原体，ATL是一种CD4+T细胞的侵袭性克隆性恶性肿瘤。HTLV-I编码一种调节蛋白Tax，它负责HTLV-I的转化潜力。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控基因和调节细胞信号通路的能力。我们最近证实，TAX通过G1期刺激细胞周期进程，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Tax的细胞进入S期，在DNA修复完成之前启动DNA复制，创造了一个促进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。综上所述，这些观察结果为税收中介转型提供了一个有趣的模型，将通过这次续签申请进一步研究。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，从而增加细胞突变频率，增强细胞转化的潜力。此应用的具体目的是：(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损伤的S时相进入的后果。(3)确定税收对突变频率和细胞转化的影响。这些研究的结果将确定HTLV-I转化特定过程中的关键步骤，并可能为细胞增殖和转化的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.