1: Mol Cell Biol. 1998 Jun;18(6):3620-32. 

Human T-cell leukemia virus type 1 Tax and cell cycle progression: role of
cyclin D-cdk and p110Rb.

Neuveut C, Low KG, Maldarelli F, Schmitt I, Majone F, Grassmann R, Jeang KT.

Laboratory of Molecular Microbiology, National Institute of Allergy and
Infectious Diseases, Bethesda, Maryland 20892-0460, USA.

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).

PMID: 9584203 [PubMed - indexed for MEDLINE]


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