Transcriptional Regulation of HTLV Gene Expression

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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.