Human T-cell leukemia virus type-l (HTLV-I) is a human exogenous retrovirus linked to adult T-cell leukemia and lymphoma(ATL). In addition to structural genes, the HTLV-I genome contains regions encoding a protein termed tat (also px, p40 or Tax) capable of activating transcription from the viral promoter in the long terminal repeat (LTR). Considerable research is now being focused on the mechanisms through which viral transactivating factors result in neoplastic transformation. Recently, a transgenic mouse model was developed to study HTLV-I related disease. Tumors developed in all mice expressing the tat protein; however, the tumors were not of lymphoid origin. This proposal seeks to study at the molecular level whether TAT induced neoplasia is specific for one tissue type or may be manipulated through selective tissue specific enhancers to develop tumors of lymphoid origin. For this purpose the interleukin 2 enhancer and the major histocompatability complex class I enhancer will be used in separate constructions with the HTLV-l TAT gene. Additional studies will focus on the pathways which lead to pathology observed in other tissue types such as the proliferation of ductal cells in the salivary gland of HTLV-I TAT transgenic mice. Preliminary data suggests that several growth factors may be stimulated by the elevated levels of Tat protein expressed in affected tissues. The mechanisms for increasing tat expression through TAT gene copy number as compared to integrated TAT transgene structure will be explored through immunoblot analysis of proteins and restriction enzyme mapping of the transgenic animal DNA.
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