Role of human T‐cell leukemia virus type I Tax in expression of the human telomerase reverse transcriptase ( hTERT ) gene in human T‐cells

The viral product Tax encoded by human T‐cell leukemia virus type I (HTLV‐I) is thought to play a central role in leukemogenesis. Clonal expansion of HTLV‐I‐infected cells requires the extension of cell division with telomere maintenance, which is regulated by the ribonucleoprotein enzyme telomerase. However, the roles of Tax in the expression of telomerase activity in T‐cells remains controversial. Our previous study indicated that expression of the human telomerase reverse transcriptase subunit ( hTERT ) gene, which determines telomerase activity, is tightly regulated in human T‐cells. In the present study, we investigated Tax‐mediated regulation of hTERT gene expression by Tax in human T‐cells. HTLV‐I Tax induced expression of the hTERT gene in human peripheral blood leukocytes. Reporter assays revealed that Tax activated the hTERT promoter in quiescent Kit 225 cells, while the promoter activity was repressed by Tax in proliferating Jurkat cells. Both up‐regulation and down‐regulation by Tax were mediated through the 43‐bp sequences in the promoter, which carried at least two elements that independently functioned as repressors. The two elements bound distinct factors. G1 to S phase transition induced by introduction of either cyclin D2 with cdk4 or p130‐specific shRNA also activated the hTERT promoter, implying that activation of the hTERT promoter in quiescent Kit 225 cells is associated with cell cycle progression. Our findings suggest that the cell cycle state critically influences Tax‐mediated regulation of hTERT expression. ( Cancer Sci 2008; 99: 1155–1163)