MECHANISM OF CELLULAR TRANSFORMATION BY HTLV-1 TAX

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Human T-cell leukemia virus type I (HTLV-I) is the etiologic agent of adult T cell leukemia (ATL), an aggressive clonal malignancy of CD4+ T cells. HTLV-I encodes a regulatory protein, Tax, which is responsible for the transforming potential of HTLV-I. Tax transformation depends upon its ability to activate cellular growth regulatory genes, although the precise mechanism of transformation remains unknown. We have recently demonstrated that Tax can activate expression of the proliferating cell nuclear antigen (PCNA) promoter. PCNA is a required co-factor of DNA polymerase delta, and its expression is intimately linked to cell growth and transformation. PCNA coordinately regulates both DNA replication and repair via a complex series of stoichiometric interactions with cell cycle regulatory proteins. Aberrant PCNA expression is thought to uncouple replication and repair activities such that DNA can be replicated before repair is complete. Thus, activation of PCNA expression by Tax may contribute to cellular proliferation and abnormal repair of damaged DNA, ultimately resulting in oncogenic transformation. The proposed studies will determine the mechanism of Tax transactivation of the human PCNA promoter. In addition, the effects of Tax activated PCNA gene expression on the accumulation of cellular DNA damage and transformation will be investigated.