Molecular basis on E2F acitivation by HTLV-I Tax

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The transactivator protein Tax of human T-cell leukemia virus type I (HTLV-I) plays an important role in the development of adult T-cell leukemia. It has been shown that Tax modulates expression and activity of many of growth regulatory molecules and genes including p16^<INK4a>. The molecular mechanism of leukemogenesis induced by Tax is yet to be elucidated, however. We have previously shown that Tax activated endogenous E2F activity in a cell type-dependent and p16^<INK4a> -independent manner in IL-2 starved Kit 225 cells, which can undergo cell cycle arrest at G0/G1 phase by deprivation of IL-2. The ability of Tax mutants to activate E2F coincided with that to activate NF-κB and NF-AT sole expression of which, however, did not activate E2F, suggesting involvement of another pathway in activation of E2F.Introduction of Tax by a recombinant adenovirus induced cell cycle progression to G2/M phase in resting Kit 225 cells accompanied by endogenous cyclin D2 gene expression. Similarly Tax-induced cell cycle progression was seen with peripheral blood cells prestimulated with phytohemagglutinin. Analyses with Tax mutants did not allow Tax-induced cell cycle progression to be differentiated from Tax-dependent activation of E2F, suggesting that Tax induces cell cycle progression presumably through activation of E2F.Nevertheless, infection with an E2F1 expressing virus, which is sufficient for induction of S phase in serum starved fibroblasts, was not stufficient for either E2F activation or cell cycle progression in IL-2 starved Kit 225 cells, implying differential regulation of E2F activation and cell cycle progression in T cells that is activated by Tax. Tax induced phosphorylation and degradation of p130, a repressor of E2F at G0/G1 phase of Kit225 cells.