STIMULATION OF CYCLIN-DEPENDENT KINASE-ACTIVITY AND G(1)-PHASE TO S-PHASE TRANSITION IN HUMAN-LYMPHOCYTES BY THE HUMAN T-CELL LEUKEMIA LYMPHOTROPIC VIRUS TYPE-1 TAX PROTEIN/

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 i t is transforming in vitro and induces tumors in transgenic animals. A lthough the transcriptional modulation of viral and cellular gene expr ession by Tax has been analyzed thoroughly, it has remained unclear ho w the Tax functions act on the cell cycle of primary T cells. To inves tigate the mechanism of Tax-mediated T-cell stimulation, we transduced primary human cord blood T cells with a conditional, tetracycline rep ressor-based tax expression system, Permanent Tax expression results i n an abnormal proliferation of T cells which closely resemble HTLV-1-i nfected lymphocytes. Suppression of Tax synthesis stopped lymphocyte g rowth and caused cell cycle arrest in the G(1) phase. Upon reinduction of tax expression, the arrested cells entered the S phase. This showe d that Tax has mitogenic activity, which is required for stimulating t he G(1)- to S-phase transition of immortalized lymphocytes. In mammali an cells, the G(1)-phase progression is controlled by the serial activ ation of several cyclin-dependent kinases (Cdks), starting with Cdk4 a nd Cdk6. In the presence of Tax, both Cdk4 and Cdk6 were activated, Th e suppression of Tax synthesis, however, resulted in a significant red uction of the Cdk4 and Cdk6 activities but did not influence the expre ssion of Cdk4, Cdk6, or cognate D-type cyclin proteins. These data sug gest that Tax induces Cdk4 and Cdk6 activity in primary human T lympho cytes; this Cdk activation is likely to account for the mitogenic Tax effect and for the abnormal T-cell proliferation of HTLV-1-infected ly mphocytes.