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Human T-cell leukemia virus type 1 is etiologically linked to the development of adult T-cell leukemia and various human neuropathies. The Tax protein of human T-cell leukemia virus type I has been implicated in cellular transformation. Like other oncoproteins, such as Myc, Jun, and Fos, Tax is a transcriptional activator. How it mechanistically dysregulates the cell cycle is unclear. Previously, it was suggested that Tax affects cell-phase transition by forming a direct protein-protein complex with p16INK4a , thereby inactivating an inhibitor of G 1 -to-S-phase progression. Here we show that, in T cells deleted for p16 INK4a , Tax can compel an egress of cells from G 0 /G 1 into S despite the absence of serum. We also show that in undifferentiated myocytes, expression of Tax represses cellular differentiation. In both settings, Tax expression was found to increase cyclin D-cdk activity and to enhance pRb phosphorylation. In T cells, a Tax-associated increase in steady-state E2F2 protein was also documented. In searching for a molecular explanation for these observations, we found that Tax forms a protein-protein complex with cyclin D3, whereas a point-mutated and transcriptionally inert Tax mutant failed to form such a complex. Interestingly, expression of wild-type Tax protein in cells was also correlated with the induction of a novel hyperphosphorylated cyclin D3 protein. Taken together, these findings suggest that Tax might directly influence cyclin D-cdk activity and function, perhaps by a route independent of cdk inhibitors such as p16 INK4a.Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent for adult T-cell leukemia and various neurological disorders termed HTLV-1-associated myelopathy (HAM) and tropical spastic paraparesis (TSP) (reviewed in reference 36). HTLV-1 encodes a 40-kDa trans-activator protein, Tax, which activates transcription through three 21-bp cyclic AMP responsive elements found in the viral long terminal repeat (LTR;6,10,22,39,78). Tax has been implicated as the critical viral protein for transformation of T cells (90). Tax induces tumors and leukemia in transgenic mice in vivo and immortalizes cultured T cells (1,4,24,25,28,29,38,54,59,69,75).The exact mechanism through which Tax exerts its oncogenic potential is not known. It is known, however, that Tax can modulate the expression of several cellular genes that are involved in cellular proliferation. For example, Tax upregulates the expression of interleukin-2, interleukin-2 receptor, c-fos, c-Jun, erg-1, and granulocyte-macrophage colony-stimulating factor (1,4,24,25,38,54,69,75). Tax can also repress the expression of ␤-polymerase, the p53 promoter, and some functions of c-myc and Bax (7,40,71,85). Additionally, Tax can cooperate with oncoproteins, such as Ras, in cellular transformation (65) and can induce morphological changes in cells via its association with intermediate filaments (83). Tax also associates with other cellular proteins (42, 60; reviewed in reference 23). How these findings fit together into the ...

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Human T-cell leukemia virus (HTLV) types I and II are highly related viruses that differ in disease manifestations. HTLV-I has been linked unmistakably to adult T-cell leukemia-lymphoma. On the other hand, there is little evidence that prior infection with HTLV-II increases risk for lymphoproliferative disorders. Both viruses encode homologous transcriptional-activating proteins (respectively designated as Tax1 and Tax2) which have been suggested to be important mediators of viral pathogenesis. Previously, we reported that Tax1 is a potent inducer of micronuclei formation in cells. Here, we present evidence that Tax2 lacks micronuclei inductive ability. We contrast this phenotypic difference between Tax1 and Tax2 at the cellular level with their similarities at the molecular level in transcriptional activation.