Submitted January 22, 2008
Accepted May 6, 2008
Central role of PI3K in transcriptional activation of hTERT in HTLV-I infected cells
Marcia Bellon and Christophe Nicot*
Microbiology, Immunology and Molecular Genetics, University of Kansas Medical Center, Kansas City, KS, United States
* Corresponding author; email: cnicot{at}kumc.edu.
The persistence of human T-cell leukemia/lymphoma virus-I (HTLV-I) infected cells is dependent upon clonal expansion and up-regulation of telomerase (hTERT). We have previously found that in IL-2-independent transformed HTLV-I cells, Tax strongly activates the hTERT promoter through NF-
B-mediated Sp1 and c-Myc activation. In IL-2-dependent cells and ATLL patient samples, however, Tax expression is very low to undetectable, yet these cells retain strong telomerase activity. This suggests the existence of compensatory mechanisms in IL-2-dependent cells and ATLL patients. In this study, we demonstrate that telomerase activity is significantly decreased upon IL-2 withdrawal in immortalized HTLV-I cell lines. Inhibition of PI3K or AKT signaling pathways noticeably reduced telomerase activity in HTLV-I cells. We found that IL-2/IL-2R signaling was associated with a PI3K-dependent/AKT-independent transcriptional up-regulation of the endogenous hTERT promoter. We also found that the Wilm's Tumor (WT1) protein strongly suppressed hTERT promoter expression and that activation of the PI3K pathway promotes cytoplasmic retention of WT1, thereby inhibiting WT1 binding to the hTERT promoter. The importance of this regulatory pathway for telomerase expression is underscored by the findings that the PI3K pathway is commonly found activated in cancer cells.
