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J Virol, January 1998, p. 633-640, Vol. 72, No. 1
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Stimulation of Cyclin-Dependent Kinase Activity and G1- to S-Phase Transition in Human Lymphocytes by the Human T-Cell Leukemia/Lymphotropic Virus Type 1 Tax Protein

Iris Schmitt,1 Oliver Rosin,1 Peter Rohwer,2 Manfred Gossen,3 and Ralph Grassmann1,*

Institut für Klinische und Molekulare Virologie der Friedrich-Alexander Universität Erlangen-Nürnberg1 and Institut für Klinische Immunologie der Friedrich-Alexander Universität Erlangen-Nürnberg,2 91054 Erlangen, and Zentrum für Molekularbiologie, 69120 Heidelberg,3 Germany

Received 12 May 1997/Accepted 14 October 1997

The human T-cell leukemia/lymphotropic virus type 1 (HTLV-1) induces a malignant lymphocytic disease. The HTLV-1 transactivator protein, Tax, is believed to be crucial for the development of the disease since it is transforming in vitro and induces tumors in transgenic animals. Although the transcriptional modulation of viral and cellular gene expression by Tax has been analyzed thoroughly, it has remained unclear how the Tax functions act on the cell cycle of primary T cells. To investigate the mechanism of Tax-mediated T-cell stimulation, we transduced primary human cord blood T cells with a conditional, tetracycline repressor-based tax expression system. Permanent Tax expression results in an abnormal proliferation of T cells which closely resemble HTLV-1-infected lymphocytes. Suppression of Tax synthesis stopped lymphocyte growth and caused cell cycle arrest in the G1 phase. Upon reinduction of tax expression, the arrested cells entered the S phase. This showed that Tax has mitogenic activity, which is required for stimulating the G1- to S-phase transition of immortalized lymphocytes. In mammalian cells, the G1-phase progression is controlled by the serial activation of several cyclin-dependent kinases (Cdks), starting with Cdk4 and Cdk6. In the presence of Tax, both Cdk4 and Cdk6 were activated. The suppression of Tax synthesis, however, resulted in a significant reduction of the Cdk4 and Cdk6 activities but did not influence the expression of Cdk4, Cdk6, or cognate D-type cyclin proteins. These data suggest that Tax induces Cdk4 and Cdk6 activity in primary human T lymphocytes; this Cdk activation is likely to account for the mitogenic Tax effect and for the abnormal T-cell proliferation of HTLV-1-infected lymphocytes.

* Corresponding author. Mailing address: Institut für Klinische und Molekulare Virologie der Friedrich-Alexander Universität Erlangen-Nürnberg, Schlossgarten 4, 91054 Erlangen, Germany. Phone: 49-9131-856784. Fax: 49-9131-852101. E-mail: rfgrassm{at}viro.med.uni-erlangen.de.




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