Over the past decade, there has been increasing evidence for the involvement of retroviruses in a variety of human diseases. The association was first made in 1978 between human T-lymphotropic virus type 1 (HTLV-1) and adult T-cell leukemia. Despite the identification of HTLV-1 more than ten years ago, many questions related to its pathogenicity in humans have remained unanswered because of the lack of appropriate animal models. The long term goals of this proposal are to define the role of the regulatory genes of HTLV-1 in inducing malignancies in transgenic mice, and to apply these transgenic mouse models toward the understanding of the molecular mechanisms for multistage carcinogenesis in humans. This application is composed of five specific aims: [1] specific targeting of the HTLV-1 tax gene to induce T-cell leukemia in mice for the purpose of deriving a useful animal model to study T-cell malignancies; [2] dissection of the product of the tax gene by deletional analysis in transgenic mice to obtain an understanding of the structure-function relationship of this viral regulatory protein; [3] functional demonstration of the interaction between the products of the HTLV-1 tax and rex genes in the control of the expression and functions of cellular genes in transgenic mice; [4] systematic survey by physical methods of cellular genes whose activation or suppression by tax leads to the development of benign proliferative disorders; and [5] identification and characterization of cellular genes secondary to tax trans-activation which are responsible for the acquisition of a malignant state of growth. It is anticipated that the murine models derived from this proposal will facilitate our understanding of human malignancies by directly addressing the role of cancer-causing genes in inducing multistage carcinogenesis.
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