Human T-Cell Leukemia Virus Type 1 Tax and Cell Cycle Progression: Role of Cyclin D-cdk and p110Rb

Abstract

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 ...

The Nuclear Protein p34SEI-1 Regulates the Kinase Activity of Cyclin-Dependent Kinase 4 in a Concentration-Dependent Manner

“…Under our in vitro assay conditions, p34 SEI-1 acts as both an activator and inhibitor of CDK4, which distinguishes p34 SEI-1 from other CDK4-binding proteins. INK4 (5)(6)(7)(8)(9)(10)(11) and KIP proteins (12)(13)(14) only inhibit CDK4; gankyrin functions as a competitor to antagonize INK4 proteins (17), while Tax is competent in activating CDK4 (15,16), quenching p16 (32,33), and affecting cyclin Ds (34). It is important to point out that most of these studies were performed by in vitro or cell-based studies, and their biological relevance remains to be established.…”

HTLV-I Tax transrepresses the human c-Myb promoter independently of its interaction with CBP or p300

“…In HTLV-I-infected cells, Tax inhibits cellular proteins that regulate cell cycle checkpoints, such as p16 ink4A , p21 waf1/cip1 , p53, and MAD-1 (Suzuki et al, 1996;Cereseto et al, 1996;Akagi et al, 1997;PiseMasison et al, 1998;Mulloy et al, 1998;Jin et al, 1998). Furthermore, Tax induces cyclin D2 upregulation and the consequent hyper-phosphorylation of the retinoblastoma (Rb) protein and constitutive cyclin E-CDK2 activity (Neuveut et al, 1998;Cereseto et al, 1999). Thus, it is tempting to speculate that, in HTLV-I-infected T-cells, Tax may override the physiological role of c-Myb in cell cycle progression.…”

Molecular and cellular aspects of HTLV-1 associated leukemogenesis in vivo

“…Indeed, Tax protein induces the expression of numerous genes involved in the differentiation and the proliferation of T cells. 59,60 Through the functional inactivation of P16 INKA4 , 61 and the activation of cyclin D2 62 and cyclin D3, 63 Tax intervenes directly in the pathway controlling T cell proliferation. Furthermore, the N terminus of Tax has recently been found to directly and specifically interact with CDK4, resulting in a Tax/CDK holoenzyme complex that capably phosphorylates the Rb protein.…”