Tax-dependent stimulation of G(1) phase-specific cyclin-dependent kinases and increased expression of signal transduction genes characterize HTLV type 1-transformed T cells

Human T cell leukemia virus protein induces T cells to permanent IL-2-depen dent growth. These cells occasionally convert to factor independence. The v iral oncoprotein Tax acts as an essential growth factor of transformed lymp hocytes and stimulates the cell cycle in the G(1) phase. Tn T cells and fib roblasts Tax enhances the activity of the cyclin-dependent kinases (CDK) CD K4 and CDK6, These kinases, which require binding to cyclin D isotypes for their activity, control the G(1) phase. Coimmunoprecipitation from these ce lls revealed that Tax associates with cyclin D3/CDK6, suggesting a direct a ctivation of this kinase, The CDK stimulation may account in part for the m itogenic Tax effect, which causes IL-2-dependent T cell growth by Tax. To a ddress the conversion to IL-2-independent proliferation and to identify ove rexpressed genes, which contribute to the transformed growth, the gene expr ession patterns of HTLV-1-transformed T cells were compared with that of pe ripheral blood lymphocytes. Potentially overexpressed cDNAs were cloned, se quenced, and used to determine the RNA expression, Genes found to be up-reg ulated are involved in signal transduction (STAT5a, cyclin G(1), c-fgr, hPG T) and also glycoprotein synthesis (LDLC, ribophorin). Many of these are al so activated during T cell activation and implicated in the regulation of g rowth and apoptosis, The transcription factor STAT5a, which is involved in IL-2 signaling, was strongly up-regulated only in IL-2-independent cells, t hus suggesting that it contributes to factor-independent growth. Thus, the differentially expressed genes could cooperate with the Tax-induced cell cy cle stimulation in the maintenance of IL-2-dependent and IL-2-independent g rowth of HTLV-transformed lymphocytes.