Activation of cyclin D1 and D2 promoters by human T-cell leukemia virus type I tax protein is associated with IL-2-independent growth of T cells

Our aim was to examine the involvement of G1 cell-cycle regulators in cell growth dysregulation induced by HTLV-I. Compared to uninfected cells, higher expression levels of cyclin D1 and D2 mRNA were detected in HTLV-I–infected T-cell lines, which were at least in part mediated by the viral transforming protein Tax since Tax activated both cyclin D1 and D2 promoters in the human T-cell line Jurkat. A Tax mutant that did not activate NF-{kappa}B failed to activate cyclin D1 and D2 promoters. Inhibitors of NF-{kappa}B (dominant negative I{kappa}Bs mutants) suppressed Tax-dependent activation of cyclin D1 and D2 promoters, indicating that Tax-induced activation was mediated by NF-{kappa}B. Wild-type and mutant Tax capable of activating NF-{kappa}B, but not Tax mutant incapable of activating NF-{kappa}B, converted cell growth of a T-cell line from being IL-2–dependent to being IL-2–independent; and this conversion was associated with IL-2–independent induction of cyclins D1 and D2. Our data suggest that induction of cyclins D1 and D2 by Tax is involved in IL-2–independent cell-cycle progression as well as IL-2–independent transformation of primary human T cells by HTLV-I. High expression levels of cyclin D1 and D2 mRNAs were also detected in some patients with ATL. Our findings link HTLV-I infection to changes in cellular D-type cyclin gene expression, transformation of T cells and subsequent development of T-cell leukemia.