Class II major histocompatibility antigens are important in T-B cell interaction and lymphocyte activation/differentiation. These antigens are constitutively expressed by resting B cells but not T cells. Interestingly, T cells infected with the Type I human leukemia virus (HTLV-I) express class II antigens concurrent with the onset of tumorgenicity. A major goal of this proposal is to understand how HTLV-I viral product can activate HLA-DR genes. Another major goal is to examine the molecular mechanisms that result in DR expression in transformed B cell lines and normal primary B cells. We have obtained preliminary evidence that the transactivating gene product, tat-I, of HTLV-I can trans-activate DR alpha upstream promoters. The precise sequences that are responsive to tat-I activation will be mapped by gene transfer of deletion mutants. The levels (transcriptional, post-transcriptional, or translational) at which tat-I is regulating these sequences will also be determined. Previous studies in our laboratory have shown that there are two regulatory elements important for DR expression in transformed B cells. Both of these bind to nuclear proteins. In this proposal, a structure-function analysis will be performed for these two elements. In addition, in vitro transcriptional assays will be used to directly assess if the proteins that bind to these elements have functional roles. Finally, and most importantly, untransformed primary B cells will be examined to deermine if they use identical regulatory pathways as transformed B cells. These experiments are intimately related to the process of leukemogenesis. The induction of DR by HTLV-I product represents a model system to examine the regulation of a cellular gene by viral products that may be oncogenic in nature. Studies of transformed and normal B cells will allow us to determine if transformation results in altered pathways of gene regulation.
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