No abstract

The role of the X region of the genome of the human T-cell leukemia virus type I (HTLV-I) in the hmmortalization of lymphocytes has been difficult to distinguish from its role in viral replication as this region encodes at least two genes, tax and rex, required for replication and the expression of viral proteins. To determine whether the X region does encode immortalizing functions, a fragment of the HTLV-I provirus capable of expressing known X-region proteins was inserted into the genome of a transformation-defective, replication-competent Herpesvirus saimiri. Infection of fresh mitogen-activated human cord blood and thymocytes yielded immortal T-cell lines that had the same phenotype (CD4+, CD5+, HLA class HII, interleukin 2 receptor a-chain +) as lymphocytes transformed by cocultivation with HTLV-I. These experiments demonstrate that the X region encodes the functions of HTLV-I that immortalize a distinct subpopulation of human T cells. The experiments also demonstrate the utility of the H.saimiri vector for the transduction of heterologous genes into human T cells.

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 ...

Background: Human T-lymphotropic virus type 1 (HTLV-1) is the etiologic agent of a severe and fatal lymphoproliferative disease of mainly CD4 + T cell origin, adult T cell leukemia, which develops after prolonged viral persistence. Transformation of infected cells involves HTLV-1's oncoprotein Tax, which perturbs cell cycle regulation and modulates cellular gene expression. The latter function is also a hallmark of microRNAs, a rather new layer in the regulation of gene expression. Affecting e.g. proliferation, microRNAs constitute a potential target for viral interference on the way to persistence and transformation. Hence, we explored the interconnections between HTLV-1 and cellular microRNAs.

The Tax The deregulation of the enzymatic machinery that controls the G 1 -to S-phase transition is causatively linked with viral transformation and tumorigenesis. Many viral oncoproteins from herpesviruses (vCyc and kCyc), adenoviruses (E1A), and papovaviruses (simian virus 40 [SV40] large T antigen and human papillomavirus E7) affect G 1 -specific cyclin-dependent kinases (CDKs) and/or their cognate substrate, retinoblastoma (Rb) protein (pRb) (22,25,50). CDK4 and its close relative CDK6 bind to cyclin D isotypes and, together with CDK2 complexes, integrate mitogenic and growth-inhibitory signals.