Transcriptional Regulation of HTLV Gene Expression

性状（由申请人提供）：人T细胞白血病病毒I型 HTLV-1是成人T细胞白血病的病原体。HTLV-I编码一种 40 kDa的非结构蛋白Tax，它是病毒转化蛋白， 在转录水平调节病毒和细胞基因表达。 由于Tax作为一种病毒致癌基因发挥作用， 与调节宿主细胞转录机制是相当重要的 兴趣DNA不是独立的DNA。相反，税收与 细胞转录因子，如CREB，将其募集到特定的 发起人。Tax还与许多细胞共激活因子相互作用， 具有内在激活和酶特性（例如CBP/p300，P/CAF）。 总之，它与细胞转录因子和辅激活因子的相互作用 导致大型多蛋白复合物的组装， 税务管理可用信息的选定子集的转录的能力 启动子和转化细胞。我们在了解 通过证明合作互动， 与细胞蛋白质，包括CREB及其辅激活因子CBP/p300，导致 Tax反式激活复合物（DNA：CREB：Tax：CBP/p300）的组装， 最佳的税务活动。Tax transactivation复合物 仅在潜在CREB结合位点的子集上，并且这种结合位点的组装 复合物指定相关启动子的转录活性。的 拟议的研究是基于这样一个假设，即税收transactivation取决于 在组装多组分反式激活复合物时， 染色质结构通过组蛋白乙酰转移酶（HAT）活性。具体 这项建议的目的是： (1)确定组装功能性蛋白质所需的蛋白质相互作用 税务激活复合体。 (2)表征Tax反式激活复合物在染色质中的作用 环境 (3)确定细胞内含CRE基因的Tax反式激活是否 与特定的Tax transactivation复合物的组装相关。 这些研究的结果将提供必要的信息， 理解Tax反式激活的分子机制和 HTLV-I转化中的细胞基因表达。

DESCRIPTION (provided by applicant): Human T cell leukemia virus type I (HTLV-l) is the etiologic agent of adult T cell leukemia. HTLV-I encodes a 4OkDa non-structural protein, Tax, which is the viral transforming protein and regulates viral and cellular gene expression at the level of transcription. Because Tax functions as a viral oncogene, the mechanism by which it interacts with and regulates the host cell transcription machinery is of considerable interest. Tax does not bind DNA independently. Rather, Tax associates with cellular transcription factors such as CREB that recruit it to specific promoters. Tax also interacts with a number of cellular coactivators that possess intrinsic activation and enzymatic properties (e.g. CBP/p300, P/CAF). Together, its interactions with cellular transcription factors and coactivators result in the assembly of large multiprotein complexes that play a central role in the ability of Tax to regulate transcription of a select subset of available promoters, and to transform cells. We have made progress in understanding the mechanism of Tax transactivation by demonstrating that cooperative interactions with cellular proteins including CREB and its coactivator, CBP/p300, result in the assembly of a Tax transactivation complex (DNA:CREB:Tax:CBP/p300) that is necessary for optimal Tax activity. The Tax transactivation complex assembles on only a subset of potential CREB binding sites, and the assembly of this complex specifies transcriptional activity of the associated promoter. The proposed studies are based on the hypothesis that Tax transactivation depends upon assembly of a multi-component transactivation complex that can influence chromatin structure via histone acetyl transferase (HAT) activity. The specific aims of this proposal are to: (1) Determine what protein interactions are required to assemble a functional Tax transactivation complex. (2) Characterize effects of the Tax transactivation complex in a chromatin environment. (3) Determine whether Tax transactivation of cellular CRE-containing genes is associated with the assembly of a specific Tax transactivation complex. The results of these studies will provide information essential for understanding the molecular mechanism of Tax transactivation and the role of cellular gene expression in HTLV-I transformation.