Human T cell leukemia virus type I (HTLV-1) is the etiologic agent of two human diseases, adult T cell leukemia and tropical spastic paraparesis/HTLV-I associated myelopathy. In addition to structural proteins, HTLV-I encodes a 40 kd 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 the host cell transcription machinery is of considerable interest. Tax does not bind to DNA directly, but does associate indirectly with DNA via binding to cellular transcription factors. Through these associations, Tax has been shown to increase the dimerization and DNA binding affinity of a diverse group of cellular transcription factors. It is interactions with, and effects on cellular proteins appear to play a central role in the ability of Tax to activate transcription. Progress has been made in understanding the mechanism of Tax transactivation by demonstration that the association of Tax with an appropriate promoter is not sufficient for maximal transactivation. Studies further demonstrate that cooperative interactions with cellular proteins including CREB and its co-activator, CBP, are necessary for optimal Tax transactivation. In addition, it has been found that cellular proteins can adopt altered conformations when bound to certain Tax-responsive DNA sequences. The proposed studies are based on the hypothesis that Tax transactivation depends upon assembly of a multi-component transactivation complex and the interactions of this complex with the basal transcription machinery.
The specific aims of the proposal are as follows: (1) determine what protein interactions are required to assemble a functional Tax transactivation complex, (2) determine how the Tax transactivation complex interacts with the basal transcription machinery, (3) determine the effects of CREB conformation on its interactions with Tax and DNA, (4) determine the basal target element of Tax transaction. The results of these studies will provide information essential for understanding the molecular mechanism of Tax transactivation and will have potential implications in viral pathogenesis.
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