Transcriptional Regulation by the HTLV-1 Tax Protein

Colorado State University-Fort Collins, Fort Collins CO

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Abstract

[unreadable] DESCRIPTION (provided by applicant): The human T-cell leukemia virus type I (HTLV-I) is a retrovirus that is the causative agent of a variety of clinical disorders, including an aggressive and fatal T-cell leukemia. Malignant transformation associated with HTLV-I infection is strongly linked to the synthesis of the virally-encoded transcription factor Tax. The Tax protein is critical to the life cycle of the virus, as it plays a major role in the transition from viral latency to high-level virion production. Tax mediates this transition via strong activation of HTLV-I transcription, which leads to efficient replication of the virus. Viral gene expression is stimulated following the formation of a stable promoter-bound complex containing Tax, the cellular transcription factor CREB and the cellular coactivators CBP/p300. Much of our current understanding of Tax-activated HTLV-I transcription has come from in vitro binding and transient transfection assays, neither of which directly assess physiological relevance of the interactions under study. In this application, we propose to explore the transcriptional regulation of the natural, chromosomally-integrated proviruses in HTLV-I infected T-cells. These studies will investigate the dynamic interaction between Tax, cellular transcription factors and coactivators at the HTLV-I promoter in living cells. We will also characterize the kinetics of transcription complex assembly, transcriptional activation and RNA synthesis, following Tax induction in human T-cells. This experimental approach is designed to mimic the in vivo events that occur during the Tax-mediated exit from viral latency. In the HTLV-I-infected T-cell, Tax also interacts with a variety of cellular transcription factors, resulting in deregulated expression of cellular genes involved in programmed cell death and cell cycle progression. This pleiotropic deregulation likely accounts for the tight link between Tax expression and malignant transformation. Of the cellular transcription factors targeted by Tax, the NF-kB proteins likely play the most prominent role in mediating Tax-deregulated cellular gene expression linked to malignant transformation. We propose to biochemically characterize the mechanisms of Tax deregulation via the NF-kB proteins by focusing on the events that occur directly at the promoters of NF-kB-responsive genes. We propose to biochemically characterize the interactions between Tax, the NF-kB proteins, and the variety of cellular coactivators utilized by these activators. Together these studies provide a diverse, integrated approach to the study of Tax function, both in vitro and in vivo. Our studies should yield a greater understanding of the multiple mechanisms of Tax transcriptional activation in the HTLV-I-infected T-cell. [unreadable] [unreadable] [unreadable]