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 p16^INK4a, thereby inactivating an inhibitor of G₁-to-S-phase progression. Here we show that, in T cells deleted for p16^INK4a, Tax can compel an egress of cells from G₀/G₁ 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.

ACKNOWLEDGMENTS

We thank M. Benkirane, R. Chun, V. Giordano, D. Jin, I. Quinto, E. Rich, and H. Xiao for critical readings of manuscript. We thank C. J. Sherr for the pGEX-p19 and pGEX-p18 plasmids.

R.G. and I.S. were supported by DGF (SFB-466).

ADDENDUM IN PROOF

Recently we have demonstrated that Tax can subvert a cellular M-phase checkpoint (D. Jin et al., Cell 93:81–91, 1998).