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Mol Cell Biol, June 1998, p. 3620-3632, Vol. 18, No. 6
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

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

Christine Neuveut,1 Kenneth G. Low,2 Frank Maldarelli,1 Iris Schmitt,3 Franca Majone,4 Ralph Grassmann,3 and Kuan-Teh Jeang1,*

Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20892-04601; Institute of Gene Therapy and Molecular Medicine, Mount Sinai School of Medicine, New York, New York 10029-65742; Dipartimento di Biologia, Universita Degli Studi di Padova, Padova, Italy4; and Institut für Klinishe und Molekulare Virologie, Erlangen, Germany3

Received 16 December 1997/Accepted 24 February 1998

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 G1-to-S-phase progression. Here we show that, in T cells deleted for p16INK4a, 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 p16INK4a.

* Corresponding author. Mailing address: Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, Bldg. 4, No. 302, 900 Rockville Pike, Bethesda, MD 20892-0460. Phone: (301) 496-6680. Fax: (301) 480-3686. E-mail: kj7e{at}nih.gov.

Mol Cell Biol, June 1998, p. 3620-3632, Vol. 18, No. 6
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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