CREB/ATF-dependent repression of cyclin a by human T-cell leukemia virus type 1 Tax protein

Expression of the human T-cell leukemia virus type 1 (HTLV-1) oncoprotein T ax is correlated with cellular transformation contributing to the developme nt of adult T-cell leukemia. Tax has been shown to modulate the activities of several cellular promoters. Existing evidence suggests that Tax need not directly bind to DNA to accomplish these effects but rather that it can ac t through binding to cellular factors, including members of the CREB/ATF fa mily. Exact mechanisms of HTLV-1 transformation of cells have yet to be ful ly defined, but the process is likely to include both activation of cellula r-growth-promoting factors and repression of cellular tumor-suppressing fun ctions. While transcriptional activation has been well studied, transcripti onal repression by Tax, reported recently from several studies, remains les s well understood. Here, we show that Tax represses the TATA-less cyclin A promoter. Repression of the cyclin A promoter was seen in both ts13 adheren t cells and Jurkat T lymphocytes, Two other TATA-less promoters, cyclin D3 and DNA polymerase alpha, were also found to be repressed by Tax. Interesti ngly, all three promoters share a common feature of at least one conserved upstream CREB/ATF binding site. In electrophoretic mobility shift assays, w e observed that Tax altered the formation of a complex(es) at the cyclin A promoter-derived ATF site. Functionally, we correlated removal of the CREB/ ATF site from the promoter with loss of repression by Tax. Furthermore, sin ce a Tax mutant protein which binds CREB repressed the cyclin A promoter wh ile another mutant protein which does not bind CREB did not, we propose tha t this Tax repression occurs through protein-protein contact with CREB/ATF.